{"gene":"CCR6","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1997,"finding":"CCR6 (then called GPR-CY4) is the specific receptor for the chemokine LARC/CCL20: LARC induced calcium flux and migration in cells stably expressing GPR-CY4, and LARC-SEAP fusion protein bound specifically to GPR-CY4-expressing cells with a Kd of 0.9 nM. No other tested CC chemokines (MCP-1, RANTES, MIP-1α, MIP-1β, TARC) competed for this binding.","method":"Calcium mobilization assay, chemotaxis assay, ligand-binding assay with SEAP-fusion protein in stably transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted receptor-ligand interaction in stably expressing cells with multiple orthogonal functional assays (Ca2+ flux, migration, saturation binding), foundational identification paper","pmids":["9169459"],"is_preprint":false},{"year":2000,"finding":"CCR6 is required for dendritic cell localization to the subepithelial dome of Peyer's patches and for normal mucosal humoral immune responses; CCR6-knockout mice lack CD11c+CD11b+ DCs in the subepithelial dome, have impaired IgA responses to oral antigens/rotavirus, and show 2–15-fold increases in intestinal T-cell subpopulations, while systemic responses remain normal.","method":"CCR6 knockout mouse analysis, immunohistochemistry, immune challenge with oral antigen and rotavirus","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype and functional immune readout, replicated in concordant study (PMID:11254677)","pmids":["10843382"],"is_preprint":false},{"year":2001,"finding":"CCR6 deficiency results in underdeveloped Peyer's patches lacking myeloid CD11b+CD11c+ DCs in the subepithelial dome, increased intestinal T-cell numbers, exaggerated contact hypersensitivity responses, and absent delayed-type hypersensitivity responses, demonstrating CCR6 is required for proper DC and T-cell trafficking in cutaneous and intestinal immunity.","method":"CCR6 knockout mouse model, histology, CHS and DTH assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts, replicates and extends findings from PMID:10843382","pmids":["11254677"],"is_preprint":false},{"year":2000,"finding":"CCR6 expression on B cells is acquired upon maturation into naive/memory B cells and is absent from germinal center B cells and plasma cells; CCL20/MIP-3α induces vigorous B-cell transmigration with preferential chemotaxis of IgD− memory B cells, establishing functional CCR6-dependent chemotaxis in B-cell subsets.","method":"Flow cytometry, transmigration chemotaxis assays across defined B-cell differentiation stages","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional chemotaxis assay with clear developmental staging, single lab","pmids":["11001880"],"is_preprint":false},{"year":2000,"finding":"TNF-α induces CCR6 expression on cytokine-activated neutrophils, rendering them functionally responsive to its ligand LARC/CCL20 (demonstrated by 125I-LARC binding and dose-dependent migration); IFN-γ induces lower CCR6 levels and the two cytokines act synergistically.","method":"Northern blot, 125I-labeled LARC binding assay, chemotaxis assay, neutralizing antibody experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct radioligand binding plus functional chemotaxis, single lab","pmids":["11090084"],"is_preprint":false},{"year":2002,"finding":"CCR6 is expressed predominantly on myeloid (CD11b+) but not lymphoid (CD8α+) dendritic cell subsets, on all mature B cells, and on subsets of T cells, as demonstrated by a CCR6-EGFP knock-in reporter mouse; CD4+ myeloid DCs are uniformly CCR6+, and Langerhans cells express CCR6 at lower levels.","method":"CCR6-EGFP knock-in mouse, flow cytometry, bone marrow culture","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct reporter knock-in providing cell-type-specific localization with functional in vivo context, multiple cell populations characterized","pmids":["11754009"],"is_preprint":false},{"year":2001,"finding":"IL-10 maintains CCR6 expression during Langerhans cell development and induces CCR6 on monocytes, while IL-4 transiently suppresses CCR6 (reversible blockade of LC differentiation) and IFN-γ irreversibly downregulates CCR6 coincident with DC maturation; TGF-β triggers irreversible CCR6 downregulation during terminal LC differentiation.","method":"In vitro cytokine stimulation of DC precursors, flow cytometry, functional CCL20 responsiveness assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cytokine conditions with functional readout (CCL20 responsiveness), single lab","pmids":["11698430"],"is_preprint":false},{"year":2004,"finding":"CCR6 expressed on polarized intestinal epithelial cells (predominantly apically) signals via Gαi proteins upon apical CCL20 stimulation: it induces tyrosine phosphorylation of p130Cas (Crk-associated substrate) and inhibits cAMP production and cAMP-mediated chloride secretion; pertussis toxin abolishes cAMP inhibition, confirming Gαi coupling.","method":"Polarized T84/Caco-2/HT-29/HCA-7 cell lines, apical stimulation with CCL20, pertussis toxin inhibition, p130Cas phosphorylation assay, cAMP/chloride secretion measurements","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro signaling reconstitution with mechanistic perturbation (pertussis toxin), two orthogonal downstream readouts (p130Cas phosphorylation; cAMP/Cl− secretion), single lab","pmids":["15483227"],"is_preprint":false},{"year":2005,"finding":"CCR6 on donor CD4+ T cells is required for their migration to and infiltration of target tissues (skin, gut) in graft-versus-host disease; CCR6-deficient donors showed reduced skin/gut CD4+ infiltration, delayed lesion onset, milder pathology, and lower IFN-γ, IL-10, and homing-chemokine levels in target organs.","method":"Allogeneic GvHD mouse models (MHC class II-mismatched and MHC-matched/miHA-mismatched), CCR6-knockout donors, histopathology, cytokine measurement","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with tissue-level cellular and molecular phenotype, single lab","pmids":["15774622"],"is_preprint":false},{"year":2008,"finding":"CCR6 expression in Th17 cells is regulated by TGF-β and requires the nuclear receptors RORα and RORγ; Th17 cells also produce the CCR6 ligand CCL20 (induced synergistically by TGF-β and IL-6 via STAT3, RORγ, and IL-21), enabling autocrine/paracrine CCR6-dependent recruitment. CCR6-deficient Th17 cells show reduced recruitment into EAE inflammatory tissues and reduced disease severity.","method":"In vitro differentiation of Th17 cells, nuclear receptor overexpression/knockout, CCR6-deficient mice in EAE model, in vitro migration assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with disease model, in vitro mechanistic dissection of transcriptional regulation and functional migration, multiple orthogonal methods","pmids":["19050256"],"is_preprint":false},{"year":2009,"finding":"CCR6 ligands (CCL20 and β-defensins) induce expression of the HIV restriction factor APOBEC3G in CCR6+ CD4+ T cells through a Gαi-dependent pathway (blocked by pertussis toxin), providing a post-entry mechanism of HIV inhibition in CCR6+ cells.","method":"APOBEC3G induction assay in CCR6+ vs. CCR6− cells, pertussis toxin inhibition, HIV infection assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway identified with pertussis toxin perturbation and cell-subset specificity, single lab","pmids":["20023216"],"is_preprint":false},{"year":2010,"finding":"CCR6 on regulatory T cells marks colon-tropic, IL-10-producing iTregs; CCR6-deficient iTregs have impaired suppressive capacity in a T-cell transfer colitis model despite equivalent frequency in lymph nodes and colon, and CCR6+ Tregs preferentially migrate to the inflamed colon.","method":"Rag2−/− T-cell transfer colitis model, CCR6-KO mice, cotransfer experiments, flow cytometry, cytokine measurements","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in disease model with co-transfer epistasis, single lab","pmids":["20720211"],"is_preprint":false},{"year":2011,"finding":"CCR6 on plasmacytoid dendritic cells (pDCs) is acquired after IL-3-driven instruction in lymphoid tissues (following initial CCR7 upregulation), enabling CCR6-dependent homing of pDCs to inflamed epithelia; competitive adoptive transfer in CCR6-deficient mice confirmed that CCR6 is required for pDC homing to inflamed skin tumors.","method":"Competitive adoptive transfer of WT vs. CCR6-deficient pDCs, imiquimod skin tumor model, IL-3 culture induction, flow cytometry","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive adoptive transfer with genetic KO provides direct mechanistic localization evidence, single lab","pmids":["21937703"],"is_preprint":false},{"year":2011,"finding":"CCR6 promotes atherogenesis by supporting monocyte homeostasis in blood and direct CCL20-induced monocyte chemotaxis: Ccr6−/−ApoE−/− mice have ~40% less aortic lesion area with 44% less macrophage content; CCL20 induces chemotaxis of WT but not Ccr6−/− primary monocytes; bone marrow transplant from Ccr6−/− donors into ApoE−/− mice recapitulates the atheroprotection.","method":"Ccr6−/−ApoE−/− double-KO mice, bone marrow transplantation, in vitro monocyte chemotaxis assay, CCL20 injection in vivo (monocytosis assay), lesion quantification","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo approaches (full KO, BM chimera) plus in vitro chemotaxis, single lab with rigorous controls","pmids":["21680896"],"is_preprint":false},{"year":2012,"finding":"CCR6 mediates positioning of Th17 cells near bile ducts in the inflamed liver: cholangiocytes stimulated by cytokines secrete CCL20, which induces CCR6-dependent migration of Th17 cells; CCR6 blockade in vitro reduces Th17 migration toward cholangiocyte-conditioned medium.","method":"In vitro chemotaxis assay with CCR6-blocking antibody, CXCR3 antibody blockade in vivo (intravital microscopy), flow cytometry of liver-infiltrating cells","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional migration assay with antibody blockade plus in vivo intravital microscopy, single lab","pmids":["22796894"],"is_preprint":false},{"year":2013,"finding":"CCR6 is required for accumulation of IL-17/IL-22-expressing γδ T cells in injured liver; Ccr6−/− mice develop more severe fibrosis with enhanced immune infiltration in chronic liver injury models (CCl4 and MCD diet); adoptive transfer of WT (but not CD4) γδ T cells into Ccr6−/− mice reduces hepatic inflammation and fibrosis to WT levels; hepatic γδ T cells promote HSC apoptosis via Fas-ligand in a cell-contact-dependent, IL-17-independent manner.","method":"Ccr6−/− mice in chronic liver injury models, adoptive transfer of γδ vs. CD4 T cells, flow cytometry, in vitro HSC apoptosis assay, Il-17−/− cell transfer","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with two disease models, adoptive transfer epistasis, mechanistic in vitro cell-contact assay, multiple orthogonal methods","pmids":["23959575"],"is_preprint":false},{"year":2013,"finding":"CCR6 on Th17 cells mediates migration to the ocular surface in dry eye disease via CCL20 expressed by the conjunctival epithelium; subconjunctival neutralization of CCL20 reduces in vitro T-cell migration and decreases conjunctival Th17 infiltration and inflammatory cytokines in vivo.","method":"CCR6-KO mice, dry eye disease model, in vitro chemotaxis assay with CCL20-neutralizing antibody, subconjunctival antibody administration in vivo, flow cytometry","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo antibody blockade with functional cellular readout, single lab","pmids":["23702781"],"is_preprint":false},{"year":2014,"finding":"CCR6 in mouse sperm is localized predominantly to the sperm tail and is functional: human sperm exhibit directional chemotaxis and motility changes toward CCL20 in vitro, and CCR6 ligands (including CCL20 and DEFB29) are present in reproductive tract fluids.","method":"Immunofluorescence and immunoblot for CCR6 in mouse and human sperm, RT-PCR for Ccr6/Defb29 mRNA in testis/epididymis, protein chip analysis of reproductive fluids, in vitro sperm chemotaxis assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional chemotaxis assay, single lab","pmids":["23765988"],"is_preprint":false},{"year":2014,"finding":"CCL20-CCR6 interactions promote spontaneous intestinal tumorigenesis: CCR6KO-ApcMin/+ mice have diminished tumor number and normalized spleen size compared to ApcMin/+ mice; CCR6 loss reduces macrophage infiltration into adenomas; CCL20 signaling through CCR6 increases CCL20 production by colorectal cancer cells (autocrine loop) and has a direct mitogenic effect on cancer cells.","method":"CCR6-KO × ApcMin/+ mouse cross, tumor quantification, macrophage infiltration immunostaining, CCL20 stimulation of cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in spontaneous tumor model with in vitro mechanistic follow-up, single lab","pmids":["24866282"],"is_preprint":false},{"year":2015,"finding":"PLZF (encoded by ZBTB16) is a transcriptional activator that regulates CCR6 expression in human Th17 cells: PLZF binds enhancer-like sites at −9/−10 and −13/−14 kb upstream of the CCR6 transcription start site (by ChIP), and ZBTB16 knockdown downregulates CCR6 and other Th17 genes; PLZF and RORγt cross-regulate each other, and PLZF binds at the RORC promoter in CCR6+ cells.","method":"ChIP for modified histones, p300, and PLZF; siRNA knockdown of ZBTB16 in human T cells; transcriptome analysis; CCR6 expression monitoring","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP with direct promoter/enhancer binding evidence plus functional knockdown, multiple orthogonal methods, single lab","pmids":["25833398"],"is_preprint":false},{"year":2016,"finding":"CCR6 on B cells negatively regulates germinal center entry: CCR6-deficient mice show accelerated GC appearance, increased dark zone/light zone ratio, decreased antigen-specific IgG1 and IgG2a (but not IgM) in a B-cell-intrinsic manner in mixed bone marrow chimeras; CCR6 is rapidly upregulated on activated B cells and only activated B cells migrate toward CCL20.","method":"Mixed bone marrow chimeras (WT vs. CCR6-KO), flow cytometry for GC kinetics and DZ/LZ ratio, ELISA for antigen-specific antibodies, in vitro CCL20 migration assay","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BM chimera approach establishes B-cell intrinsic function; multiple readouts, single lab","pmids":["27465674"],"is_preprint":false},{"year":2017,"finding":"CCR6 signaling inhibits iTreg suppressor function and directs Treg-to-Th17 lineage conversion: CCL20 inhibits TGF-β1-induced iTreg differentiation in a CCR6-dependent manner, reduces surface expression of suppressor molecules (CD39, CD73, FasL), impairs suppressive function, and induces phosphorylation of Akt, mTOR, and STAT3.","method":"In vitro Treg differentiation assays with/without CCL20 and CCR6 blockade, flow cytometry for Treg markers, phospho-western blots for Akt/mTOR/STAT3, suppression assays","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional suppression assay with signaling mechanism (phosphorylation), CCR6-dependency confirmed, single lab","pmids":["29126851"],"is_preprint":false},{"year":2017,"finding":"CCR6 is required for ligand-induced CatSper-dependent Ca2+ influx in human sperm: CCR6 co-localizes and co-immunoprecipitates with CatSper; siRNA knockdown of either CCR6 or CatSper abolishes Ca2+ influx induced by DEFB1, CCL20, and progesterone; this Ca2+ pathway is required for sperm motility, hyperactivation, and acrosome reaction, which are impaired in infertile sperm with reduced CCR6/CatSper levels.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, siRNA knockdown, Ca2+ current measurements, sperm functional assays (motility, hyperactivation, acrosome reaction)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + functional siRNA knockdown with physiological readout, single lab","pmids":["29207656"],"is_preprint":false},{"year":2018,"finding":"Somatic truncating mutations (nonsense and frameshift) in CCR6 cluster in the C-terminal cytoplasmic tail in MALT lymphomas; these mutations are predicted to remove the phosphorylation motif required for β-arrestin-mediated receptor desensitization and internalization, suggesting gain-of-constitutive signaling.","method":"Whole exome sequencing of MALT lymphoma samples, bioinformatic analysis of mutation clustering","journal":"Haematologica","confidence":"Low","confidence_rationale":"Tier 4 / Weak — sequencing only, functional consequence inferred but not experimentally validated","pmids":["29674500"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of human CCR6 bound to its endogenous ligand CCL20 and an engineered Gαo protein at 3.3 Å resolution shows CCL20 binds in a shallow extracellular pocket making limited contact with the 7-TM core; this binding allosterically rearranges a noncanonical toggle switch and opens the intracellular crevice for G protein coupling, demonstrating that protein-agonist GPCR activation does not always require deep 7-TM interactions.","method":"Cryo-electron microscopy structure determination at 3.3 Å, structural analysis of activation mechanism","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structure with mechanistic interpretation of activation mechanism, peer-reviewed in high-impact journal","pmids":["32541785"],"is_preprint":false},{"year":2016,"finding":"CCL20/CCR6 promotes tumor angiogenesis in colorectal cancer via the AKT/NF-κB/VEGF-A pathway: CCR6 silencing decreases HUVEC proliferation and migration, while CCR6 overexpression promotes angiogenesis; mechanistically, CCR6 activation leads to AKT/NF-κB pathway activation and increased VEGF-A secretion.","method":"CCR6 siRNA knockdown and overexpression in CRC cells, HUVEC proliferation and migration assays, AKT/NF-κB signaling analysis, in vivo angiogenesis assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with downstream signaling analysis, single lab","pmids":["29097259"],"is_preprint":false},{"year":2016,"finding":"CCL20/CCR6 signaling regulates bone mass accrual: Ccr6−/− mice have significantly decreased trabecular bone mass with reduced osteoblast numbers; CCL20 and CCR6 are co-expressed in osteoblast progenitors and upregulated during differentiation; CCR6 acts as a functional Gprotein-coupled receptor in osteoblasts; CCR6 loss inhibits osteoblast differentiation (markers, alkaline phosphatase, mineralization); CCL20 promotes osteoblast survival via PI3K-AKT; Ccl20−/− mice recapitulate the bone loss phenotype confirming specificity.","method":"μCT and histomorphometry in Ccr6−/− and Ccl20−/− mice, osteoblast differentiation assays, AKT phosphorylation assays, macrophage/T-cell recruitment assays","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO lines (CCR6 and CCL20) with concordant phenotype, in vitro mechanistic dissection with signaling pathway, multiple orthogonal readouts","pmids":["26890063"],"is_preprint":false},{"year":2019,"finding":"Cisplatin-stimulated macrophages promote ovarian cancer cell migration via CCL20 secretion activating CCR6 on cancer cells, triggering epithelial-to-mesenchymal transition; pharmacological CCL20 blockade on macrophages and siRNA-mediated CCR6 silencing in cancer cells abrogated migration induced by cisplatin-stimulated macrophages.","method":"Macrophage-cancer cell co-culture, cisplatin stimulation, CCL20 ELISA, siRNA CCR6 knockdown, migration assays, EMT marker analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with functional migration readout and mechanistic (EMT) markers, single lab","pmids":["31866467"],"is_preprint":false},{"year":2017,"finding":"In CTCL, STAT3 is spontaneously activated and transcribes CCL20; CCL20 then signals through CCR6 in an autocrine manner to drive migration; knockdown of STAT3, CCL20, or CCR6, or CCL20 neutralizing antibody, all reduce CTCL cell migration in vitro; CCL20-neutralizing antibody prolongs survival of CTCL xenograft mice.","method":"STAT3/CCL20/CCR6 siRNA knockdown, CCL20 neutralizing antibody, in vitro migration assay, NOD/SCID xenograft mouse survival","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown cascade plus in vivo antibody efficacy, single lab","pmids":["26789110"],"is_preprint":false},{"year":2022,"finding":"SMAD4 loss in colon epithelium increases CCL20 expression and chemoattracts CCR6+ immune cells (T regulatory, Th17, dendritic cells), promoting colitis-associated carcinogenesis; genetic deletion of Ccr6 abrogated these immune responses and significantly reduced tumor incidence in Smad4-conditional KO mice.","method":"Conditional colon-epithelial Smad4 KO mice with/without germline Ccr6 deletion, colitis model, tumor quantification, flow cytometry, immunostaining","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO epistasis establishes CCR6 as downstream effector of SMAD4 tumor suppression, multiple readouts, single lab with human tissue validation","pmids":["35863523"],"is_preprint":false},{"year":2024,"finding":"Two inactive CCR6 structures determined by cryo-EM reveal two allosteric antagonist binding pockets: an extracellular pocket occupied by oxomorpholine antagonists (OXM1/OXM2) that disrupt the receptor activation network, and an intracellular pocket occupied by squaramide SQA1 that overlaps with the G protein binding site, stabilizing a closed (inactive) conformation; minimal allosteric cooperativity between the two pockets was observed.","method":"Cryo-EM structural determination of two ternary CCR6/SQA1/OXM complexes, pharmacological characterization of antagonist binding","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures with mechanistic interpretation of two distinct antagonist mechanisms, peer-reviewed","pmids":["39217154"],"is_preprint":false},{"year":2024,"finding":"CCR6-CCL20 signaling in tumor-infiltrating Tregs promotes glycolysis and lactate production, which is required for their immunosuppressive activity toward CD8+ T cells; Ccr6−/− Tregs show reduced glycolysis and lactic acid production with compensatory glutamine metabolism; Ccr6−/− mice show improved survival across multiple tumor models and enhanced anti-PD-1 efficacy in glioma.","method":"Ccr6-KO mice in multiple tumor models, metabolic assays (glycolysis, lactate, glutamine), CD8 T-cell suppression assays, anti-PD-1 combination therapy, CCL20 siRNA knockdown","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with metabolic mechanism and functional suppression assay, single lab with multiple tumor models","pmids":["39133127"],"is_preprint":false},{"year":2022,"finding":"CCR6 deficiency in CCR6−/− mice strongly ameliorates radiation-induced alopecia and dermatitis (IRIAD); IL-6 deficiency reduces CCL20 and CCR6 upregulation, while CCR6 deficiency reciprocally reduces IL-6, IL-17, CCL3, and MHC upregulation, revealing a proximity-dependent cellular cross-talk loop amplifying radiation dermatitis.","method":"CCR6−/− mice, IL-6−/− mice, IL-1R−/− mice, scRNA-seq, genetic ablation studies, molecular inhibitor studies (JAK blockers, cyclosporine)","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic KO lines with mechanistic pathway cross-validation by scRNA-seq, single lab","pmids":["35785521"],"is_preprint":false},{"year":2015,"finding":"CrkL adapter protein mediates CCL20/CCR6-induced epithelial-to-mesenchymal transition in gastric cancer via the Akt pathway (not ERK1/2): CCL20 activates p-CrkL, p-ERK1/2, p-Akt, vimentin, N-cadherin and MMP2 in a dose-dependent manner; si-CrkL ablates CCL20-induced vimentin, N-cadherin, MMP2 and migration/invasion, but does not affect p-ERK1/2.","method":"siRNA knockdown of CrkL, CCL20 stimulation dose-response, western blot for signaling pathway components, migration/invasion assays","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA dissection of downstream signaling, gain/loss of function, single lab","pmids":["26044596"],"is_preprint":false},{"year":2009,"finding":"CCL20/MIP-3α accounts for ~40% of RA synovial fluid chemotactic activity for monocytes; in vitro monocyte chemotaxis induced by MIP-3α is inhibited by pertussis toxin pretreatment of monocytes, confirming signaling through a Gi-coupled receptor.","method":"Modified Boyden chamber monocyte chemotaxis assay, pertussis toxin inhibition, ELISA, flow cytometry","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional chemotaxis with mechanistic pertussis toxin perturbation, single lab","pmids":["12695561"],"is_preprint":false},{"year":2013,"finding":"CCR6 selectively promotes monocyte (but not T cell) adhesion to inflamed endothelium and monocyte recruitment in an acute air-pouch inflammatory model; CCR6 reduces circulating Gr-1high and Gr-1low monocytes in Ccr6−/−Ldlr−/− mice, establishing a role for CCR6 in monocyte mobilization, adhesion, and chemotaxis that drives atherosclerosis.","method":"Ccr6−/−Ldlr−/− double-KO mice, in vitro monocyte adhesion assay to inflamed endothelium, in vivo air pouch monocyte recruitment model, flow cytometry","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with KO mice, single lab","pmids":["24114205"],"is_preprint":false},{"year":2023,"finding":"PF-07054894 is a CCR6 antagonist that binds with slow dissociation kinetics (slower off-rate for CCR6 vs. CCR7/CXCR2) producing insurmountable inhibition of CCL20/CCR6-mediated human T-cell chemotaxis; oral administration in cynomolgus monkeys increases circulating CCR6+ T cells (consistent with blockade of homeostatic tissue egress); the compound also causes upregulation of cell-surface CCR6 in B cells in vivo and in vitro.","method":"β-arrestin GPCR panel screen (168 receptors), human T-cell chemotaxis assay, [3H]-PF-07054894 radioligand binding/dissociation kinetics, in vivo primate pharmacology, IL-23 mouse skin model","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — radioligand binding kinetics plus in vitro and in vivo functional validation, single lab","pmids":["37142443"],"is_preprint":false},{"year":2022,"finding":"CCR6 in endometriosis: CCR6 binds TFEB in ESCs (co-IP confirmed), inhibiting TFEB nuclear translocation, thereby blocking lysosomal function and autophagic flux (autolysosome degradation), which promotes ESC proliferation and migration; macrophage-derived CCL20 activates this CCR6-TFEB pathway in co-culture.","method":"Co-immunoprecipitation (CCR6/TFEB), TFEB nuclear translocation assay, mRFP-GFP-LC3 autophagic flux reporter, lysosome function assays (Lyso-tracker, Gal3, acid phosphatase), CCL20-neutralizing antibody in vivo mouse model","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional nuclear translocation and autophagic flux assays, single lab","pmids":["35841069"],"is_preprint":false}],"current_model":"CCR6 is a Gαi-coupled seven-transmembrane chemokine receptor whose primary ligand CCL20 (and β-defensins as secondary ligands) induces Gαi-mediated signaling (inhibition of cAMP, p130Cas phosphorylation, Akt/mTOR/STAT3 and AKT/NF-κB/VEGF pathway activation), driving directed chemotaxis of immature dendritic cells, Th17 cells, regulatory T cells, B cells, monocytes, and γδ T cells to sites of CCL20 expression at epithelial/mucosal surfaces and sites of inflammation; its cryo-EM structure reveals that CCL20 activates the receptor via a shallow extracellular binding mode that allosterically rearranges a noncanonical toggle switch to open the G protein-coupling crevice, while allosteric small-molecule antagonists occupy either an extracellular pocket disrupting this activation network or an intracellular pocket overlapping the G protein site; beyond chemotaxis, CCR6 signaling regulates osteoblast differentiation and survival via PI3K-AKT, controls iTreg-to-Th17 lineage plasticity, modulates Treg glycolysis and immunosuppressive function, interacts with CatSper to mediate Ca2+ influx and chemotaxis in sperm, and associates with TFEB to block autophagic flux in endometriotic stromal cells."},"narrative":{"mechanistic_narrative":"CCR6 is a Gαi-coupled seven-transmembrane chemokine receptor that directs chemotaxis of immune and epithelial cell populations toward its specific ligand CCL20/LARC, governing mucosal and inflammatory tissue homing [PMID:9169459, PMID:15483227]. CCL20 binds CCR6 with nanomolar affinity and selectively triggers calcium flux and directed migration; cryo-EM of the CCL20–CCR6–Gαo complex shows the ligand engaging a shallow extracellular pocket that allosterically rearranges a noncanonical toggle switch to open the intracellular G-protein crevice, a non-deep mode of protein-agonist activation [PMID:9169459, PMID:32541785]. Downstream of pertussis-toxin-sensitive Gαi, CCR6 inhibits cAMP production and phosphorylates p130Cas, and through Akt/mTOR/STAT3 and AKT/NF-κB/VEGF signaling shapes cell migration, survival, and lineage decisions [PMID:15483227, PMID:29126851, PMID:29097259]. CCR6 is required for trafficking of myeloid dendritic cells to the Peyer's-patch subepithelial dome and for mucosal IgA immunity, and for recruitment of Th17 cells, IL-10-producing colon-tropic iTregs, B cells, neutrophils, plasmacytoid DCs, monocytes, and γδ T cells to epithelial and inflamed tissues [PMID:11254677, PMID:11754009, PMID:19050256, PMID:20720211, PMID:21680896, PMID:23959575]. Its expression is transcriptionally programmed by RORα/RORγt and PLZF (ZBTB16) in Th17 cells and dynamically tuned by cytokines such as TGF-β, IL-10, IL-4, and IFN-γ [PMID:19050256, PMID:25833398, PMID:11698430]. CCR6 signaling also acts beyond leukocyte trafficking: it promotes osteoblast differentiation and survival via PI3K-AKT [PMID:26890063], drives CCL20-dependent tumor growth, angiogenesis, EMT, and Treg-mediated immunosuppression across colorectal, ovarian, gastric, and cutaneous T-cell malignancies [PMID:24866282, PMID:29097259, PMID:35863523, PMID:39133127, PMID:26044596], mediates CatSper-dependent Ca2+ influx and chemotaxis in sperm [PMID:29207656], and associates with TFEB to block autophagic flux in endometriotic stromal cells [PMID:35841069]. High-resolution inactive-state structures define two distinct allosteric antagonist pockets, providing a template for small-molecule CCR6 inhibitors [PMID:39217154, PMID:37142443].","teleology":[{"year":1997,"claim":"Establishing the receptor's ligand identity was the foundational question; pairing CCR6 with CCL20 defined its molecular input and selectivity.","evidence":"Calcium flux, chemotaxis, and SEAP-fusion saturation binding in stably transfected cells","pmids":["9169459"],"confidence":"High","gaps":["Did not define downstream G-protein coupling","No structural basis for ligand recognition","Secondary β-defensin ligands not yet identified"]},{"year":2000,"claim":"Whether CCR6 had a non-redundant physiological role was unknown; knockout mice showed it is required for dendritic-cell positioning in the gut subepithelial dome and for mucosal humoral immunity.","evidence":"CCR6-knockout mouse immunohistochemistry and oral antigen/rotavirus challenge","pmids":["10843382","11254677"],"confidence":"High","gaps":["Molecular signaling underlying DC positioning not defined","Did not address other CCR6+ cell types","Systemic vs mucosal compartmentalization mechanism unresolved"]},{"year":2000,"claim":"Defining which cell types use CCR6 mapped the breadth of its trafficking program; mature/memory B cells, neutrophils, and myeloid DC subsets were shown to be functionally CCR6-responsive and cytokine-regulated.","evidence":"Flow cytometry, transmigration assays, radioligand binding, CCR6-EGFP knock-in reporter, and cytokine stimulation across cell types","pmids":["11001880","11090084","11754009","11698430"],"confidence":"High","gaps":["Reporter does not establish in vivo migratory function for each subset","Cytokine regulation mostly single-lab in vitro","Functional consequence of subset-specific expression varies by context"]},{"year":2004,"claim":"The receptor's signaling output was undefined; apical CCL20 stimulation of polarized epithelium showed Gαi coupling that inhibits cAMP and phosphorylates p130Cas.","evidence":"Polarized intestinal epithelial cell lines, pertussis toxin perturbation, cAMP/chloride secretion and p130Cas phosphorylation readouts","pmids":["15483227"],"confidence":"High","gaps":["Did not link signaling to specific migratory or transcriptional outputs","Single epithelial-cell context","β-arrestin / desensitization arm not addressed"]},{"year":2008,"claim":"How CCR6 expression is wired to T-helper identity was unknown; TGF-β with RORα/RORγt was shown to drive CCR6 in Th17 cells, which also make CCL20, creating an autocrine recruitment loop tied to autoimmune disease.","evidence":"In vitro Th17 differentiation, nuclear receptor gain/loss, CCR6-deficient mice in EAE, migration assays","pmids":["19050256"],"confidence":"High","gaps":["Direct transcription-factor binding at CCR6 locus not shown here","Th17 vs Treg balance not addressed","Human relevance inferred from mouse model"]},{"year":2010,"claim":"Whether CCR6 marks distinct regulatory T-cell function was open; CCR6 was shown to define colon-tropic IL-10+ iTregs whose suppressive capacity depends on the receptor.","evidence":"T-cell transfer colitis model with CCR6-KO and co-transfer experiments","pmids":["20720211"],"confidence":"Medium","gaps":["Mechanism linking CCR6 to suppressive function not defined","Single disease model","Whether effect is migration-dependent or intrinsic unclear"]},{"year":2011,"claim":"Extending CCR6 trafficking beyond lymphocytes, monocyte homeostasis and pDC homing were shown to be CCR6-dependent, implicating the receptor in atherosclerosis and inflamed-tissue surveillance.","evidence":"Ccr6−/−ApoE−/− mice, bone marrow chimeras, monocyte chemotaxis, competitive pDC adoptive transfer in skin tumor model","pmids":["21680896","21937703"],"confidence":"High","gaps":["Distinguishing monocyte mobilization from local chemotaxis requires further dissection","pDC findings single-lab","Downstream signaling in monocytes/pDCs not characterized"]},{"year":2013,"claim":"The role of CCR6 in tissue-specific inflammatory positioning was clarified across liver, eye, and vascular contexts, including a protective γδ T-cell axis driving HSC apoptosis via Fas-ligand.","evidence":"CCR6-KO mice in liver fibrosis and dry eye models, adoptive transfer epistasis, antibody blockade, monocyte adhesion assays","pmids":["23959575","23702781","24114205"],"confidence":"High","gaps":["Cell-contact apoptosis mechanism downstream of recruitment, not receptor signaling","Some readouts antibody-blockade only","Context-dependent pro- vs anti-inflammatory roles unresolved"]},{"year":2015,"claim":"Direct transcriptional control of CCR6 was established; PLZF (ZBTB16) binds upstream enhancer elements and is required for CCR6 and Th17 gene expression, cross-regulating RORγt.","evidence":"ChIP for PLZF/p300/histone marks and ZBTB16 siRNA knockdown in human Th17 cells","pmids":["25833398"],"confidence":"High","gaps":["Did not test CCR6 enhancer activity in reporter assays","Mechanism of PLZF-RORγt cross-regulation incomplete","Single-lab human T-cell system"]},{"year":2016,"claim":"CCR6 function beyond immune trafficking emerged; it drives osteoblast differentiation/survival via PI3K-AKT and promotes tumor angiogenesis through AKT/NF-κB/VEGF-A.","evidence":"Ccr6−/− and Ccl20−/− mice with µCT/histomorphometry, osteoblast differentiation and AKT assays, CRC cell knockdown/overexpression with HUVEC angiogenesis assays","pmids":["26890063","29097259"],"confidence":"High","gaps":["Cell-intrinsic osteoblast vs immune-mediated bone effect not fully separated","Angiogenesis findings single-lab","Whether bone role uses canonical Gαi chemotaxis machinery unclear"]},{"year":2017,"claim":"How CCR6 signaling shapes Treg/Th17 plasticity was addressed; CCL20-CCR6 inhibits iTreg suppressor function and drives Treg-to-Th17 conversion via Akt/mTOR/STAT3.","evidence":"In vitro Treg differentiation/suppression assays with CCR6 blockade and phospho-western blots","pmids":["29126851"],"confidence":"Medium","gaps":["In vitro only","In vivo relevance of lineage conversion not shown here","STAT3/mTOR causality not tested by pathway inhibition"]},{"year":2017,"claim":"A non-canonical CCR6 role in sperm was defined; CCR6 physically interacts with CatSper to mediate ligand-induced Ca2+ influx required for motility, hyperactivation, and acrosome reaction.","evidence":"Co-IP, co-localization, siRNA knockdown, Ca2+ current and sperm functional assays in human sperm","pmids":["29207656","23765988"],"confidence":"Medium","gaps":["Stoichiometry/structural basis of CCR6-CatSper interaction unknown","Single Co-IP without reciprocal structural validation","Whether Gαi signaling participates unclear"]},{"year":2018,"claim":"Whether CCR6 itself is somatically altered in cancer was tested; truncating mutations cluster in the C-terminal tail in MALT lymphoma, predicted to abolish β-arrestin-mediated desensitization.","evidence":"Whole exome sequencing of MALT lymphoma with bioinformatic clustering analysis","pmids":["29674500"],"confidence":"Low","gaps":["Functional consequence inferred but not experimentally validated","Constitutive signaling not demonstrated","No β-arrestin recruitment assay performed"]},{"year":2020,"claim":"The structural basis of CCR6 activation was resolved; cryo-EM showed CCL20 binds a shallow extracellular pocket and allosterically opens the G-protein crevice without deep 7-TM engagement.","evidence":"3.3 Å cryo-EM of CCL20–CCR6–engineered Gαo complex","pmids":["32541785"],"confidence":"High","gaps":["β-defensin secondary-ligand binding mode not resolved","Dynamics of toggle-switch rearrangement static-structure inferred","Did not capture inactive/antagonist states"]},{"year":2022,"claim":"CCR6 was placed downstream of epithelial tumor-suppressor loss and as an amplifier of inflammatory cross-talk; deleting Ccr6 abrogated immune recruitment in SMAD4-loss carcinogenesis and broke an IL-6/CCL20 dermatitis loop.","evidence":"Conditional Smad4-KO × Ccr6-KO epistasis with tumor quantification, and Ccr6/IL-6 KO crosses with scRNA-seq in radiation dermatitis","pmids":["35863523","35785521"],"confidence":"High","gaps":["Which CCR6+ cell type is the dominant effector not fully resolved","Cross-talk loop mechanism partly correlative","Translation to human disease inferred"]},{"year":2022,"claim":"A receptor-scaffold mechanism beyond chemotaxis was found; CCR6 binds TFEB and blocks its nuclear translocation, inhibiting autophagic flux to promote endometriotic stromal cell proliferation.","evidence":"Co-IP of CCR6/TFEB, TFEB translocation and mRFP-GFP-LC3 autophagic flux assays, CCL20-neutralizing antibody mouse model","pmids":["35841069"],"confidence":"Medium","gaps":["Direct vs indirect CCR6-TFEB binding not distinguished","Single Co-IP context","Relationship to canonical Gαi signaling unknown"]},{"year":2024,"claim":"The inactive-state pharmacology and metabolic immunosuppressive role were defined; two allosteric antagonist pockets were structurally mapped, and CCR6 was shown to drive Treg glycolysis required for CD8 suppression and immunotherapy resistance.","evidence":"Cryo-EM of inactive CCR6 with OXM and SQA1 antagonists; Ccr6-KO mice in multiple tumor models with metabolic and anti-PD-1 assays; antagonist binding-kinetics studies","pmids":["39217154","39133127","37142443"],"confidence":"High","gaps":["Minimal cooperativity between pockets limits dual-targeting strategy clarity","Metabolic mechanism single-lab","Antagonist efficacy in human disease not established"]},{"year":null,"claim":"How CCR6's diverse non-chemotactic functions (osteoblast survival, CatSper coupling, TFEB sequestration) mechanistically relate to its canonical Gαi-chemotaxis machinery, and whether they share or diverge from the structurally defined activation network, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified signaling model linking scaffold and chemotactic roles","β-arrestin/desensitization regulation not experimentally characterized in disease mutants","Cell-type-specific effector wiring undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,24]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,37]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,17,22,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,24,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,9,11,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,13,35]}],"complexes":[],"partners":["CCL20","CATSPER1","TFEB","CRKL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00421","full_name":"C-C chemokine receptor-like 2","aliases":["Chemokine receptor CCR11","Chemokine receptor X","Putative MCP-1 chemokine receptor"],"length_aa":344,"mass_kda":39.5,"function":"Receptor for CCL19 and chemerin/RARRES2. Does not appear to be a signaling receptor, but may have a role in modulating chemokine-triggered immune responses by capturing and internalizing CCL19 or by presenting RARRES2 ligand to CMKLR1, a functional signaling receptors. Plays a critical role for the development of Th2 responses","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O00421/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCR6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCR6","total_profiled":1310},"omim":[{"mim_id":"618282","title":"HYPER-IgE SYNDROME 3, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS; HIES3","url":"https://www.omim.org/entry/618282"},{"mim_id":"609817","title":"VASCULITIS, LYMPHOCYTIC, CUTANEOUS SMALL VESSEL","url":"https://www.omim.org/entry/609817"},{"mim_id":"606611","title":"DEFENSIN, BETA, 103A; DEFB103A","url":"https://www.omim.org/entry/606611"},{"mim_id":"606579","title":"VITILIGO-ASSOCIATED MULTIPLE AUTOIMMUNE DISEASE SUSCEPTIBILITY 1; VAMAS1","url":"https://www.omim.org/entry/606579"},{"mim_id":"605980","title":"NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1; NOD1","url":"https://www.omim.org/entry/605980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":31.7}],"url":"https://www.proteinatlas.org/search/CCR6"},"hgnc":{"alias_symbol":["CKR-L3","GPR-CY4","CMKBR6","GPR29","DRY-6","DCR2","BN-1","CD196"],"prev_symbol":["STRL22"]},"alphafold":{"accession":"O00421","domains":[{"cath_id":"1.20.1070.10","chopping":"40-314","consensus_level":"medium","plddt":85.2898,"start":40,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00421","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00421-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00421-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCR6","jax_strain_url":"https://www.jax.org/strain/search?query=CCR6"},"sequence":{"accession":"O00421","fasta_url":"https://rest.uniprot.org/uniprotkb/O00421.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00421/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00421"}},"corpus_meta":[{"pmid":"12948524","id":"PMC_12948524","title":"The CC chemokine CCL20 and its receptor CCR6.","date":"2003","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12948524","citation_count":665,"is_preprint":false},{"pmid":"19050256","id":"PMC_19050256","title":"CCR6 regulates the migration of inflammatory and regulatory T cells.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19050256","citation_count":443,"is_preprint":false},{"pmid":"10843382","id":"PMC_10843382","title":"CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue.","date":"2000","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10843382","citation_count":384,"is_preprint":false},{"pmid":"9169459","id":"PMC_9169459","title":"Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9169459","citation_count":353,"is_preprint":false},{"pmid":"33076281","id":"PMC_33076281","title":"CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33076281","citation_count":308,"is_preprint":false},{"pmid":"20042588","id":"PMC_20042588","title":"Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20042588","citation_count":274,"is_preprint":false},{"pmid":"15613550","id":"PMC_15613550","title":"CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15613550","citation_count":241,"is_preprint":false},{"pmid":"19830744","id":"PMC_19830744","title":"CCR6 and NK1.1 distinguish between IL-17A and IFN-gamma-producing gammadelta effector T cells.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19830744","citation_count":236,"is_preprint":false},{"pmid":"32707869","id":"PMC_32707869","title":"The CCL20-CCR6 Axis in Cancer Progression.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32707869","citation_count":214,"is_preprint":false},{"pmid":"21376174","id":"PMC_21376174","title":"CCR6 as a mediator of immunity in the lung and gut.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21376174","citation_count":196,"is_preprint":false},{"pmid":"33971346","id":"PMC_33971346","title":"CCR6-CCL20 axis as a therapeutic target for autoimmune diseases.","date":"2021","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/33971346","citation_count":184,"is_preprint":false},{"pmid":"22796894","id":"PMC_22796894","title":"CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.","date":"2012","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/22796894","citation_count":174,"is_preprint":false},{"pmid":"11254677","id":"PMC_11254677","title":"CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11254677","citation_count":169,"is_preprint":false},{"pmid":"23959575","id":"PMC_23959575","title":"Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis.","date":"2013","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23959575","citation_count":169,"is_preprint":false},{"pmid":"11001880","id":"PMC_11001880","title":"Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3alpha/CCL20 in human B cells.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11001880","citation_count":142,"is_preprint":false},{"pmid":"17057190","id":"PMC_17057190","title":"CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis.","date":"2006","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17057190","citation_count":137,"is_preprint":false},{"pmid":"27835617","id":"PMC_27835617","title":"HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy.","date":"2017","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27835617","citation_count":126,"is_preprint":false},{"pmid":"19480006","id":"PMC_19480006","title":"The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19480006","citation_count":120,"is_preprint":false},{"pmid":"11090084","id":"PMC_11090084","title":"Expression of CCR6 and CD83 by cytokine-activated human neutrophils.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11090084","citation_count":115,"is_preprint":false},{"pmid":"25828206","id":"PMC_25828206","title":"The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis.","date":"2015","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/25828206","citation_count":111,"is_preprint":false},{"pmid":"12695561","id":"PMC_12695561","title":"Role of macrophage inflammatory protein-3alpha and its ligand CCR6 in rheumatoid arthritis.","date":"2003","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12695561","citation_count":110,"is_preprint":false},{"pmid":"20954179","id":"PMC_20954179","title":"An immune paradox: how can the same chemokine axis regulate both immune tolerance and activation?: CCR6/CCL20: a chemokine axis balancing immunological tolerance and inflammation in autoimmune disease.","date":"2010","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20954179","citation_count":101,"is_preprint":false},{"pmid":"31866467","id":"PMC_31866467","title":"Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31866467","citation_count":89,"is_preprint":false},{"pmid":"32541785","id":"PMC_32541785","title":"Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32541785","citation_count":85,"is_preprint":false},{"pmid":"36045408","id":"PMC_36045408","title":"CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36045408","citation_count":83,"is_preprint":false},{"pmid":"16641550","id":"PMC_16641550","title":"Involvement of chemokine receptor CCR6 in colorectal cancer metastasis.","date":"2006","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16641550","citation_count":78,"is_preprint":false},{"pmid":"11754009","id":"PMC_11754009","title":"CCR6 expression distinguishes mouse myeloid and lymphoid dendritic cell subsets: demonstration using a CCR6 EGFP knock-in mouse.","date":"2002","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11754009","citation_count":78,"is_preprint":false},{"pmid":"32554933","id":"PMC_32554933","title":"Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/32554933","citation_count":76,"is_preprint":false},{"pmid":"30772094","id":"PMC_30772094","title":"The CCR6-CCL20 axis in humoral immunity and T-B cell immunobiology.","date":"2019","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30772094","citation_count":74,"is_preprint":false},{"pmid":"15774622","id":"PMC_15774622","title":"CCR6 regulates CD4+ T-cell-mediated acute graft-versus-host disease responses.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15774622","citation_count":72,"is_preprint":false},{"pmid":"20720211","id":"PMC_20720211","title":"CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20720211","citation_count":72,"is_preprint":false},{"pmid":"23702781","id":"PMC_23702781","title":"The CCR6/CCL20 axis mediates Th17 cell migration to the ocular surface in dry eye disease.","date":"2013","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/23702781","citation_count":66,"is_preprint":false},{"pmid":"26811629","id":"PMC_26811629","title":"Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview.","date":"2016","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26811629","citation_count":65,"is_preprint":false},{"pmid":"38942796","id":"PMC_38942796","title":"Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38942796","citation_count":64,"is_preprint":false},{"pmid":"21949768","id":"PMC_21949768","title":"Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21949768","citation_count":64,"is_preprint":false},{"pmid":"30453514","id":"PMC_30453514","title":"Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer.","date":"2018","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/30453514","citation_count":62,"is_preprint":false},{"pmid":"23765988","id":"PMC_23765988","title":"A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis.","date":"2014","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23765988","citation_count":58,"is_preprint":false},{"pmid":"29097259","id":"PMC_29097259","title":"CCR6 promotes tumor angiogenesis via the AKT/NF-κB/VEGF pathway in colorectal cancer.","date":"2017","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29097259","citation_count":57,"is_preprint":false},{"pmid":"12642342","id":"PMC_12642342","title":"Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12642342","citation_count":57,"is_preprint":false},{"pmid":"29126851","id":"PMC_29126851","title":"CCR6 signaling inhibits suppressor function of induced-Treg during gut inflammation.","date":"2017","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/29126851","citation_count":55,"is_preprint":false},{"pmid":"29674500","id":"PMC_29674500","title":"Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.","date":"2018","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/29674500","citation_count":53,"is_preprint":false},{"pmid":"17171755","id":"PMC_17171755","title":"Functional expression of chemokine receptor CCR6 on human effector memory CD8+ T cells.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17171755","citation_count":53,"is_preprint":false},{"pmid":"26654242","id":"PMC_26654242","title":"Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach.","date":"2015","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/26654242","citation_count":52,"is_preprint":false},{"pmid":"24394994","id":"PMC_24394994","title":"CCR6 and CCL20: emerging players in the pathogenesis of rheumatoid arthritis.","date":"2014","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24394994","citation_count":50,"is_preprint":false},{"pmid":"20629596","id":"PMC_20629596","title":"CCR6 as a possible therapeutic target in psoriasis.","date":"2010","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/20629596","citation_count":50,"is_preprint":false},{"pmid":"26044596","id":"PMC_26044596","title":"CrkL meditates CCL20/CCR6-induced EMT in gastric cancer.","date":"2015","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/26044596","citation_count":50,"is_preprint":false},{"pmid":"24866282","id":"PMC_24866282","title":"CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24866282","citation_count":48,"is_preprint":false},{"pmid":"21680896","id":"PMC_21680896","title":"Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice.","date":"2011","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/21680896","citation_count":48,"is_preprint":false},{"pmid":"17615381","id":"PMC_17615381","title":"Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis.","date":"2007","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/17615381","citation_count":47,"is_preprint":false},{"pmid":"31796951","id":"PMC_31796951","title":"Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.","date":"2020","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31796951","citation_count":46,"is_preprint":false},{"pmid":"27149649","id":"PMC_27149649","title":"CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition.","date":"2016","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27149649","citation_count":45,"is_preprint":false},{"pmid":"21937703","id":"PMC_21937703","title":"CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21937703","citation_count":45,"is_preprint":false},{"pmid":"35863523","id":"PMC_35863523","title":"SMAD4 Suppresses Colitis-associated Carcinoma Through Inhibition of CCL20/CCR6-mediated Inflammation.","date":"2022","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/35863523","citation_count":43,"is_preprint":false},{"pmid":"26617177","id":"PMC_26617177","title":"CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.","date":"2015","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26617177","citation_count":43,"is_preprint":false},{"pmid":"20023216","id":"PMC_20023216","title":"CCR6 ligands inhibit HIV by inducing APOBEC3G.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20023216","citation_count":43,"is_preprint":false},{"pmid":"29250193","id":"PMC_29250193","title":"Role of CCL20/CCR6 and the ERK signaling pathway in lung adenocarcinoma.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29250193","citation_count":41,"is_preprint":false},{"pmid":"28600287","id":"PMC_28600287","title":"Enrichment of Human CCR6+ Regulatory T Cells with Superior Suppressive Activity in Oral Cancer.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28600287","citation_count":40,"is_preprint":false},{"pmid":"35785521","id":"PMC_35785521","title":"Single-cell transcriptomics reveals a senescence-associated IL-6/CCR6 axis driving radiodermatitis.","date":"2022","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35785521","citation_count":38,"is_preprint":false},{"pmid":"29981781","id":"PMC_29981781","title":"Expression of CCR6 and CXCR6 by Gut-Derived CD4+/CD8α+ T-Regulatory Cells, Which Are Decreased in Blood Samples From Patients With Inflammatory Bowel Diseases.","date":"2018","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/29981781","citation_count":38,"is_preprint":false},{"pmid":"25585877","id":"PMC_25585877","title":"The relationship between CCR6 and its binding partners: does the CCR6-CCL20 axis have to be extended?","date":"2015","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/25585877","citation_count":37,"is_preprint":false},{"pmid":"34702715","id":"PMC_34702715","title":"Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.","date":"2021","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/34702715","citation_count":36,"is_preprint":false},{"pmid":"36326893","id":"PMC_36326893","title":"Inhibition of the CCR6-CCL20 axis prevents regulatory T cell recruitment and sensitizes head and neck squamous cell carcinoma to radiation therapy.","date":"2022","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/36326893","citation_count":36,"is_preprint":false},{"pmid":"21195108","id":"PMC_21195108","title":"Chicken CCR6 and CCR7 are markers for immature and mature dendritic cells respectively.","date":"2010","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21195108","citation_count":36,"is_preprint":false},{"pmid":"25833398","id":"PMC_25833398","title":"PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25833398","citation_count":36,"is_preprint":false},{"pmid":"15483227","id":"PMC_15483227","title":"Chemokine receptor CCR6 transduces signals that activate p130Cas and alter cAMP-stimulated ion transport in human intestinal epithelial cells.","date":"2004","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15483227","citation_count":36,"is_preprint":false},{"pmid":"27465674","id":"PMC_27465674","title":"Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses.","date":"2016","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27465674","citation_count":35,"is_preprint":false},{"pmid":"11698430","id":"PMC_11698430","title":"IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11698430","citation_count":35,"is_preprint":false},{"pmid":"28005525","id":"PMC_28005525","title":"CCR6/CCL20 chemokine axis in human immunodeficiency virus immunity and pathogenesis.","date":"2017","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/28005525","citation_count":34,"is_preprint":false},{"pmid":"31151410","id":"PMC_31151410","title":"CCL20-CCR6 axis modulated traumatic brain injury-induced visual pathologies.","date":"2019","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/31151410","citation_count":33,"is_preprint":false},{"pmid":"27916417","id":"PMC_27916417","title":"CCL20/CCR6 promotes cell proliferation and metastasis in laryngeal cancer by activating p38 pathway.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27916417","citation_count":32,"is_preprint":false},{"pmid":"22269120","id":"PMC_22269120","title":"Investigation of JAK2, STAT3 and CCR6 polymorphisms and their gene-gene interactions in inflammatory bowel disease.","date":"2012","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22269120","citation_count":32,"is_preprint":false},{"pmid":"37092451","id":"PMC_37092451","title":"CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases.","date":"2023","source":"Antibodies (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37092451","citation_count":31,"is_preprint":false},{"pmid":"31322256","id":"PMC_31322256","title":"DEPDC1 drives hepatocellular carcinoma cell proliferation, invasion and angiogenesis by regulating the CCL20/CCR6 signaling pathway.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31322256","citation_count":31,"is_preprint":false},{"pmid":"32355189","id":"PMC_32355189","title":"Keratinocyte transglutaminase 2 promotes CCR6+ γδT-cell recruitment by upregulating CCL20 in psoriatic inflammation.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32355189","citation_count":27,"is_preprint":false},{"pmid":"20844183","id":"PMC_20844183","title":"Expression of the chemokine receptor CCR6 in human renal inflammation.","date":"2010","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/20844183","citation_count":26,"is_preprint":false},{"pmid":"24114205","id":"PMC_24114205","title":"CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice.","date":"2013","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/24114205","citation_count":26,"is_preprint":false},{"pmid":"30728405","id":"PMC_30728405","title":"Differential expression of CXCR3 and CCR6 on CD4+ T-lymphocytes with distinct memory phenotypes characterizes tuberculosis-associated immune reconstitution inflammatory syndrome.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30728405","citation_count":26,"is_preprint":false},{"pmid":"26789110","id":"PMC_26789110","title":"Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26789110","citation_count":26,"is_preprint":false},{"pmid":"32300208","id":"PMC_32300208","title":"Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32300208","citation_count":25,"is_preprint":false},{"pmid":"34497608","id":"PMC_34497608","title":"Reduced CCR6+IL-17A+Treg Cells in Blood and CCR6-Dependent Accumulation of IL-17A+Treg Cells in Lungs of Patients With Allergic Asthma.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34497608","citation_count":25,"is_preprint":false},{"pmid":"20439195","id":"PMC_20439195","title":"Expression of chemokine receptor CCR6 as a molecular determinant of adrenal metastatic relapse in patients with primary lung cancer.","date":"2010","source":"Clinical lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20439195","citation_count":25,"is_preprint":false},{"pmid":"28051083","id":"PMC_28051083","title":"The loss of CCR6+ and CD161+ CD4+ T-cell homeostasis contributes to disease progression in SIV-infected rhesus macaques.","date":"2017","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28051083","citation_count":24,"is_preprint":false},{"pmid":"27895171","id":"PMC_27895171","title":"Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27895171","citation_count":24,"is_preprint":false},{"pmid":"23835793","id":"PMC_23835793","title":"High CCR6/CCR7 expression and Foxp3+ Treg cell number are positively related to the progression of laryngeal squamous cell carcinoma.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23835793","citation_count":24,"is_preprint":false},{"pmid":"34081845","id":"PMC_34081845","title":"Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation.","date":"2021","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34081845","citation_count":23,"is_preprint":false},{"pmid":"26628988","id":"PMC_26628988","title":"The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26628988","citation_count":23,"is_preprint":false},{"pmid":"26890063","id":"PMC_26890063","title":"CCL20/CCR6 Signaling Regulates Bone Mass Accrual in Mice.","date":"2016","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/26890063","citation_count":23,"is_preprint":false},{"pmid":"12514792","id":"PMC_12514792","title":"CCR6 is a functional chemokine receptor that serves to identify select B-cell non-Hodgkin's lymphomas.","date":"2002","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12514792","citation_count":22,"is_preprint":false},{"pmid":"38902257","id":"PMC_38902257","title":"RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38902257","citation_count":21,"is_preprint":false},{"pmid":"39217154","id":"PMC_39217154","title":"Structural basis for CCR6 modulation by allosteric antagonists.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39217154","citation_count":20,"is_preprint":false},{"pmid":"37572185","id":"PMC_37572185","title":"PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment.","date":"2023","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/37572185","citation_count":20,"is_preprint":false},{"pmid":"32599163","id":"PMC_32599163","title":"Treatment with shCCL20-CCR6 nanodendriplexes and human mesenchymal stem cell therapy improves pathology in mice with repeated traumatic brain injury.","date":"2020","source":"Nanomedicine : nanotechnology, biology, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32599163","citation_count":20,"is_preprint":false},{"pmid":"29207656","id":"PMC_29207656","title":"CCR6 is required for ligand-induced CatSper activation in human sperm.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29207656","citation_count":20,"is_preprint":false},{"pmid":"19492413","id":"PMC_19492413","title":"CCL20/CCR6 chemokine/receptor expression in bone tissue from osteoarthritis and rheumatoid arthritis patients: different response of osteoblasts in the two groups.","date":"2009","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19492413","citation_count":20,"is_preprint":false},{"pmid":"33335408","id":"PMC_33335408","title":"The Role of CCL20-CCR6 Axis in Ovarian Cancer Metastasis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33335408","citation_count":19,"is_preprint":false},{"pmid":"39133127","id":"PMC_39133127","title":"The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors.","date":"2024","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/39133127","citation_count":18,"is_preprint":false},{"pmid":"24559209","id":"PMC_24559209","title":"Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells.","date":"2014","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24559209","citation_count":18,"is_preprint":false},{"pmid":"34902786","id":"PMC_34902786","title":"CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34902786","citation_count":18,"is_preprint":false},{"pmid":"37142443","id":"PMC_37142443","title":"A Novel C-C Chemoattractant Cytokine (Chemokine) Receptor 6 (CCR6) Antagonist (PF-07054894) Distinguishes between Homologous Chemokine Receptors, Increases Basal Circulating CCR6+ T Cells, and Ameliorates Interleukin-23-Induced Skin Inflammation.","date":"2023","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37142443","citation_count":18,"is_preprint":false},{"pmid":"35841069","id":"PMC_35841069","title":"CCL20/CCR6 axis mediates macrophages to promote proliferation and migration of ESCs by blocking autophagic flux in endometriosis.","date":"2022","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35841069","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53749,"output_tokens":10037,"usd":0.155901,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":41732,"output_tokens":10537,"usd":0.360802,"resynth_parse_fail":true,"stage2_stop_reason":"end_turn"},"total_usd":0.516703,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"CCR6 (then called GPR-CY4) is the specific receptor for the chemokine LARC/CCL20: LARC induced calcium flux and migration in cells stably expressing GPR-CY4, and LARC-SEAP fusion protein bound specifically to GPR-CY4-expressing cells with a Kd of 0.9 nM. No other tested CC chemokines (MCP-1, RANTES, MIP-1α, MIP-1β, TARC) competed for this binding.\",\n      \"method\": \"Calcium mobilization assay, chemotaxis assay, ligand-binding assay with SEAP-fusion protein in stably transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted receptor-ligand interaction in stably expressing cells with multiple orthogonal functional assays (Ca2+ flux, migration, saturation binding), foundational identification paper\",\n      \"pmids\": [\"9169459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CCR6 is required for dendritic cell localization to the subepithelial dome of Peyer's patches and for normal mucosal humoral immune responses; CCR6-knockout mice lack CD11c+CD11b+ DCs in the subepithelial dome, have impaired IgA responses to oral antigens/rotavirus, and show 2–15-fold increases in intestinal T-cell subpopulations, while systemic responses remain normal.\",\n      \"method\": \"CCR6 knockout mouse analysis, immunohistochemistry, immune challenge with oral antigen and rotavirus\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype and functional immune readout, replicated in concordant study (PMID:11254677)\",\n      \"pmids\": [\"10843382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CCR6 deficiency results in underdeveloped Peyer's patches lacking myeloid CD11b+CD11c+ DCs in the subepithelial dome, increased intestinal T-cell numbers, exaggerated contact hypersensitivity responses, and absent delayed-type hypersensitivity responses, demonstrating CCR6 is required for proper DC and T-cell trafficking in cutaneous and intestinal immunity.\",\n      \"method\": \"CCR6 knockout mouse model, histology, CHS and DTH assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts, replicates and extends findings from PMID:10843382\",\n      \"pmids\": [\"11254677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CCR6 expression on B cells is acquired upon maturation into naive/memory B cells and is absent from germinal center B cells and plasma cells; CCL20/MIP-3α induces vigorous B-cell transmigration with preferential chemotaxis of IgD− memory B cells, establishing functional CCR6-dependent chemotaxis in B-cell subsets.\",\n      \"method\": \"Flow cytometry, transmigration chemotaxis assays across defined B-cell differentiation stages\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional chemotaxis assay with clear developmental staging, single lab\",\n      \"pmids\": [\"11001880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TNF-α induces CCR6 expression on cytokine-activated neutrophils, rendering them functionally responsive to its ligand LARC/CCL20 (demonstrated by 125I-LARC binding and dose-dependent migration); IFN-γ induces lower CCR6 levels and the two cytokines act synergistically.\",\n      \"method\": \"Northern blot, 125I-labeled LARC binding assay, chemotaxis assay, neutralizing antibody experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct radioligand binding plus functional chemotaxis, single lab\",\n      \"pmids\": [\"11090084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCR6 is expressed predominantly on myeloid (CD11b+) but not lymphoid (CD8α+) dendritic cell subsets, on all mature B cells, and on subsets of T cells, as demonstrated by a CCR6-EGFP knock-in reporter mouse; CD4+ myeloid DCs are uniformly CCR6+, and Langerhans cells express CCR6 at lower levels.\",\n      \"method\": \"CCR6-EGFP knock-in mouse, flow cytometry, bone marrow culture\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct reporter knock-in providing cell-type-specific localization with functional in vivo context, multiple cell populations characterized\",\n      \"pmids\": [\"11754009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-10 maintains CCR6 expression during Langerhans cell development and induces CCR6 on monocytes, while IL-4 transiently suppresses CCR6 (reversible blockade of LC differentiation) and IFN-γ irreversibly downregulates CCR6 coincident with DC maturation; TGF-β triggers irreversible CCR6 downregulation during terminal LC differentiation.\",\n      \"method\": \"In vitro cytokine stimulation of DC precursors, flow cytometry, functional CCL20 responsiveness assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cytokine conditions with functional readout (CCL20 responsiveness), single lab\",\n      \"pmids\": [\"11698430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CCR6 expressed on polarized intestinal epithelial cells (predominantly apically) signals via Gαi proteins upon apical CCL20 stimulation: it induces tyrosine phosphorylation of p130Cas (Crk-associated substrate) and inhibits cAMP production and cAMP-mediated chloride secretion; pertussis toxin abolishes cAMP inhibition, confirming Gαi coupling.\",\n      \"method\": \"Polarized T84/Caco-2/HT-29/HCA-7 cell lines, apical stimulation with CCL20, pertussis toxin inhibition, p130Cas phosphorylation assay, cAMP/chloride secretion measurements\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro signaling reconstitution with mechanistic perturbation (pertussis toxin), two orthogonal downstream readouts (p130Cas phosphorylation; cAMP/Cl− secretion), single lab\",\n      \"pmids\": [\"15483227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CCR6 on donor CD4+ T cells is required for their migration to and infiltration of target tissues (skin, gut) in graft-versus-host disease; CCR6-deficient donors showed reduced skin/gut CD4+ infiltration, delayed lesion onset, milder pathology, and lower IFN-γ, IL-10, and homing-chemokine levels in target organs.\",\n      \"method\": \"Allogeneic GvHD mouse models (MHC class II-mismatched and MHC-matched/miHA-mismatched), CCR6-knockout donors, histopathology, cytokine measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with tissue-level cellular and molecular phenotype, single lab\",\n      \"pmids\": [\"15774622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCR6 expression in Th17 cells is regulated by TGF-β and requires the nuclear receptors RORα and RORγ; Th17 cells also produce the CCR6 ligand CCL20 (induced synergistically by TGF-β and IL-6 via STAT3, RORγ, and IL-21), enabling autocrine/paracrine CCR6-dependent recruitment. CCR6-deficient Th17 cells show reduced recruitment into EAE inflammatory tissues and reduced disease severity.\",\n      \"method\": \"In vitro differentiation of Th17 cells, nuclear receptor overexpression/knockout, CCR6-deficient mice in EAE model, in vitro migration assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with disease model, in vitro mechanistic dissection of transcriptional regulation and functional migration, multiple orthogonal methods\",\n      \"pmids\": [\"19050256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCR6 ligands (CCL20 and β-defensins) induce expression of the HIV restriction factor APOBEC3G in CCR6+ CD4+ T cells through a Gαi-dependent pathway (blocked by pertussis toxin), providing a post-entry mechanism of HIV inhibition in CCR6+ cells.\",\n      \"method\": \"APOBEC3G induction assay in CCR6+ vs. CCR6− cells, pertussis toxin inhibition, HIV infection assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway identified with pertussis toxin perturbation and cell-subset specificity, single lab\",\n      \"pmids\": [\"20023216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCR6 on regulatory T cells marks colon-tropic, IL-10-producing iTregs; CCR6-deficient iTregs have impaired suppressive capacity in a T-cell transfer colitis model despite equivalent frequency in lymph nodes and colon, and CCR6+ Tregs preferentially migrate to the inflamed colon.\",\n      \"method\": \"Rag2−/− T-cell transfer colitis model, CCR6-KO mice, cotransfer experiments, flow cytometry, cytokine measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in disease model with co-transfer epistasis, single lab\",\n      \"pmids\": [\"20720211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CCR6 on plasmacytoid dendritic cells (pDCs) is acquired after IL-3-driven instruction in lymphoid tissues (following initial CCR7 upregulation), enabling CCR6-dependent homing of pDCs to inflamed epithelia; competitive adoptive transfer in CCR6-deficient mice confirmed that CCR6 is required for pDC homing to inflamed skin tumors.\",\n      \"method\": \"Competitive adoptive transfer of WT vs. CCR6-deficient pDCs, imiquimod skin tumor model, IL-3 culture induction, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive adoptive transfer with genetic KO provides direct mechanistic localization evidence, single lab\",\n      \"pmids\": [\"21937703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CCR6 promotes atherogenesis by supporting monocyte homeostasis in blood and direct CCL20-induced monocyte chemotaxis: Ccr6−/−ApoE−/− mice have ~40% less aortic lesion area with 44% less macrophage content; CCL20 induces chemotaxis of WT but not Ccr6−/− primary monocytes; bone marrow transplant from Ccr6−/− donors into ApoE−/− mice recapitulates the atheroprotection.\",\n      \"method\": \"Ccr6−/−ApoE−/− double-KO mice, bone marrow transplantation, in vitro monocyte chemotaxis assay, CCL20 injection in vivo (monocytosis assay), lesion quantification\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo approaches (full KO, BM chimera) plus in vitro chemotaxis, single lab with rigorous controls\",\n      \"pmids\": [\"21680896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCR6 mediates positioning of Th17 cells near bile ducts in the inflamed liver: cholangiocytes stimulated by cytokines secrete CCL20, which induces CCR6-dependent migration of Th17 cells; CCR6 blockade in vitro reduces Th17 migration toward cholangiocyte-conditioned medium.\",\n      \"method\": \"In vitro chemotaxis assay with CCR6-blocking antibody, CXCR3 antibody blockade in vivo (intravital microscopy), flow cytometry of liver-infiltrating cells\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional migration assay with antibody blockade plus in vivo intravital microscopy, single lab\",\n      \"pmids\": [\"22796894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCR6 is required for accumulation of IL-17/IL-22-expressing γδ T cells in injured liver; Ccr6−/− mice develop more severe fibrosis with enhanced immune infiltration in chronic liver injury models (CCl4 and MCD diet); adoptive transfer of WT (but not CD4) γδ T cells into Ccr6−/− mice reduces hepatic inflammation and fibrosis to WT levels; hepatic γδ T cells promote HSC apoptosis via Fas-ligand in a cell-contact-dependent, IL-17-independent manner.\",\n      \"method\": \"Ccr6−/− mice in chronic liver injury models, adoptive transfer of γδ vs. CD4 T cells, flow cytometry, in vitro HSC apoptosis assay, Il-17−/− cell transfer\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with two disease models, adoptive transfer epistasis, mechanistic in vitro cell-contact assay, multiple orthogonal methods\",\n      \"pmids\": [\"23959575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCR6 on Th17 cells mediates migration to the ocular surface in dry eye disease via CCL20 expressed by the conjunctival epithelium; subconjunctival neutralization of CCL20 reduces in vitro T-cell migration and decreases conjunctival Th17 infiltration and inflammatory cytokines in vivo.\",\n      \"method\": \"CCR6-KO mice, dry eye disease model, in vitro chemotaxis assay with CCL20-neutralizing antibody, subconjunctival antibody administration in vivo, flow cytometry\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo antibody blockade with functional cellular readout, single lab\",\n      \"pmids\": [\"23702781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCR6 in mouse sperm is localized predominantly to the sperm tail and is functional: human sperm exhibit directional chemotaxis and motility changes toward CCL20 in vitro, and CCR6 ligands (including CCL20 and DEFB29) are present in reproductive tract fluids.\",\n      \"method\": \"Immunofluorescence and immunoblot for CCR6 in mouse and human sperm, RT-PCR for Ccr6/Defb29 mRNA in testis/epididymis, protein chip analysis of reproductive fluids, in vitro sperm chemotaxis assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional chemotaxis assay, single lab\",\n      \"pmids\": [\"23765988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCL20-CCR6 interactions promote spontaneous intestinal tumorigenesis: CCR6KO-ApcMin/+ mice have diminished tumor number and normalized spleen size compared to ApcMin/+ mice; CCR6 loss reduces macrophage infiltration into adenomas; CCL20 signaling through CCR6 increases CCL20 production by colorectal cancer cells (autocrine loop) and has a direct mitogenic effect on cancer cells.\",\n      \"method\": \"CCR6-KO × ApcMin/+ mouse cross, tumor quantification, macrophage infiltration immunostaining, CCL20 stimulation of cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in spontaneous tumor model with in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"24866282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PLZF (encoded by ZBTB16) is a transcriptional activator that regulates CCR6 expression in human Th17 cells: PLZF binds enhancer-like sites at −9/−10 and −13/−14 kb upstream of the CCR6 transcription start site (by ChIP), and ZBTB16 knockdown downregulates CCR6 and other Th17 genes; PLZF and RORγt cross-regulate each other, and PLZF binds at the RORC promoter in CCR6+ cells.\",\n      \"method\": \"ChIP for modified histones, p300, and PLZF; siRNA knockdown of ZBTB16 in human T cells; transcriptome analysis; CCR6 expression monitoring\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP with direct promoter/enhancer binding evidence plus functional knockdown, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"25833398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCR6 on B cells negatively regulates germinal center entry: CCR6-deficient mice show accelerated GC appearance, increased dark zone/light zone ratio, decreased antigen-specific IgG1 and IgG2a (but not IgM) in a B-cell-intrinsic manner in mixed bone marrow chimeras; CCR6 is rapidly upregulated on activated B cells and only activated B cells migrate toward CCL20.\",\n      \"method\": \"Mixed bone marrow chimeras (WT vs. CCR6-KO), flow cytometry for GC kinetics and DZ/LZ ratio, ELISA for antigen-specific antibodies, in vitro CCL20 migration assay\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BM chimera approach establishes B-cell intrinsic function; multiple readouts, single lab\",\n      \"pmids\": [\"27465674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCR6 signaling inhibits iTreg suppressor function and directs Treg-to-Th17 lineage conversion: CCL20 inhibits TGF-β1-induced iTreg differentiation in a CCR6-dependent manner, reduces surface expression of suppressor molecules (CD39, CD73, FasL), impairs suppressive function, and induces phosphorylation of Akt, mTOR, and STAT3.\",\n      \"method\": \"In vitro Treg differentiation assays with/without CCL20 and CCR6 blockade, flow cytometry for Treg markers, phospho-western blots for Akt/mTOR/STAT3, suppression assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional suppression assay with signaling mechanism (phosphorylation), CCR6-dependency confirmed, single lab\",\n      \"pmids\": [\"29126851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCR6 is required for ligand-induced CatSper-dependent Ca2+ influx in human sperm: CCR6 co-localizes and co-immunoprecipitates with CatSper; siRNA knockdown of either CCR6 or CatSper abolishes Ca2+ influx induced by DEFB1, CCL20, and progesterone; this Ca2+ pathway is required for sperm motility, hyperactivation, and acrosome reaction, which are impaired in infertile sperm with reduced CCR6/CatSper levels.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, siRNA knockdown, Ca2+ current measurements, sperm functional assays (motility, hyperactivation, acrosome reaction)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + functional siRNA knockdown with physiological readout, single lab\",\n      \"pmids\": [\"29207656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Somatic truncating mutations (nonsense and frameshift) in CCR6 cluster in the C-terminal cytoplasmic tail in MALT lymphomas; these mutations are predicted to remove the phosphorylation motif required for β-arrestin-mediated receptor desensitization and internalization, suggesting gain-of-constitutive signaling.\",\n      \"method\": \"Whole exome sequencing of MALT lymphoma samples, bioinformatic analysis of mutation clustering\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — sequencing only, functional consequence inferred but not experimentally validated\",\n      \"pmids\": [\"29674500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of human CCR6 bound to its endogenous ligand CCL20 and an engineered Gαo protein at 3.3 Å resolution shows CCL20 binds in a shallow extracellular pocket making limited contact with the 7-TM core; this binding allosterically rearranges a noncanonical toggle switch and opens the intracellular crevice for G protein coupling, demonstrating that protein-agonist GPCR activation does not always require deep 7-TM interactions.\",\n      \"method\": \"Cryo-electron microscopy structure determination at 3.3 Å, structural analysis of activation mechanism\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structure with mechanistic interpretation of activation mechanism, peer-reviewed in high-impact journal\",\n      \"pmids\": [\"32541785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL20/CCR6 promotes tumor angiogenesis in colorectal cancer via the AKT/NF-κB/VEGF-A pathway: CCR6 silencing decreases HUVEC proliferation and migration, while CCR6 overexpression promotes angiogenesis; mechanistically, CCR6 activation leads to AKT/NF-κB pathway activation and increased VEGF-A secretion.\",\n      \"method\": \"CCR6 siRNA knockdown and overexpression in CRC cells, HUVEC proliferation and migration assays, AKT/NF-κB signaling analysis, in vivo angiogenesis assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with downstream signaling analysis, single lab\",\n      \"pmids\": [\"29097259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL20/CCR6 signaling regulates bone mass accrual: Ccr6−/− mice have significantly decreased trabecular bone mass with reduced osteoblast numbers; CCL20 and CCR6 are co-expressed in osteoblast progenitors and upregulated during differentiation; CCR6 acts as a functional Gprotein-coupled receptor in osteoblasts; CCR6 loss inhibits osteoblast differentiation (markers, alkaline phosphatase, mineralization); CCL20 promotes osteoblast survival via PI3K-AKT; Ccl20−/− mice recapitulate the bone loss phenotype confirming specificity.\",\n      \"method\": \"μCT and histomorphometry in Ccr6−/− and Ccl20−/− mice, osteoblast differentiation assays, AKT phosphorylation assays, macrophage/T-cell recruitment assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO lines (CCR6 and CCL20) with concordant phenotype, in vitro mechanistic dissection with signaling pathway, multiple orthogonal readouts\",\n      \"pmids\": [\"26890063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cisplatin-stimulated macrophages promote ovarian cancer cell migration via CCL20 secretion activating CCR6 on cancer cells, triggering epithelial-to-mesenchymal transition; pharmacological CCL20 blockade on macrophages and siRNA-mediated CCR6 silencing in cancer cells abrogated migration induced by cisplatin-stimulated macrophages.\",\n      \"method\": \"Macrophage-cancer cell co-culture, cisplatin stimulation, CCL20 ELISA, siRNA CCR6 knockdown, migration assays, EMT marker analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional migration readout and mechanistic (EMT) markers, single lab\",\n      \"pmids\": [\"31866467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In CTCL, STAT3 is spontaneously activated and transcribes CCL20; CCL20 then signals through CCR6 in an autocrine manner to drive migration; knockdown of STAT3, CCL20, or CCR6, or CCL20 neutralizing antibody, all reduce CTCL cell migration in vitro; CCL20-neutralizing antibody prolongs survival of CTCL xenograft mice.\",\n      \"method\": \"STAT3/CCL20/CCR6 siRNA knockdown, CCL20 neutralizing antibody, in vitro migration assay, NOD/SCID xenograft mouse survival\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown cascade plus in vivo antibody efficacy, single lab\",\n      \"pmids\": [\"26789110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMAD4 loss in colon epithelium increases CCL20 expression and chemoattracts CCR6+ immune cells (T regulatory, Th17, dendritic cells), promoting colitis-associated carcinogenesis; genetic deletion of Ccr6 abrogated these immune responses and significantly reduced tumor incidence in Smad4-conditional KO mice.\",\n      \"method\": \"Conditional colon-epithelial Smad4 KO mice with/without germline Ccr6 deletion, colitis model, tumor quantification, flow cytometry, immunostaining\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO epistasis establishes CCR6 as downstream effector of SMAD4 tumor suppression, multiple readouts, single lab with human tissue validation\",\n      \"pmids\": [\"35863523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Two inactive CCR6 structures determined by cryo-EM reveal two allosteric antagonist binding pockets: an extracellular pocket occupied by oxomorpholine antagonists (OXM1/OXM2) that disrupt the receptor activation network, and an intracellular pocket occupied by squaramide SQA1 that overlaps with the G protein binding site, stabilizing a closed (inactive) conformation; minimal allosteric cooperativity between the two pockets was observed.\",\n      \"method\": \"Cryo-EM structural determination of two ternary CCR6/SQA1/OXM complexes, pharmacological characterization of antagonist binding\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures with mechanistic interpretation of two distinct antagonist mechanisms, peer-reviewed\",\n      \"pmids\": [\"39217154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCR6-CCL20 signaling in tumor-infiltrating Tregs promotes glycolysis and lactate production, which is required for their immunosuppressive activity toward CD8+ T cells; Ccr6−/− Tregs show reduced glycolysis and lactic acid production with compensatory glutamine metabolism; Ccr6−/− mice show improved survival across multiple tumor models and enhanced anti-PD-1 efficacy in glioma.\",\n      \"method\": \"Ccr6-KO mice in multiple tumor models, metabolic assays (glycolysis, lactate, glutamine), CD8 T-cell suppression assays, anti-PD-1 combination therapy, CCL20 siRNA knockdown\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with metabolic mechanism and functional suppression assay, single lab with multiple tumor models\",\n      \"pmids\": [\"39133127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCR6 deficiency in CCR6−/− mice strongly ameliorates radiation-induced alopecia and dermatitis (IRIAD); IL-6 deficiency reduces CCL20 and CCR6 upregulation, while CCR6 deficiency reciprocally reduces IL-6, IL-17, CCL3, and MHC upregulation, revealing a proximity-dependent cellular cross-talk loop amplifying radiation dermatitis.\",\n      \"method\": \"CCR6−/− mice, IL-6−/− mice, IL-1R−/− mice, scRNA-seq, genetic ablation studies, molecular inhibitor studies (JAK blockers, cyclosporine)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic KO lines with mechanistic pathway cross-validation by scRNA-seq, single lab\",\n      \"pmids\": [\"35785521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CrkL adapter protein mediates CCL20/CCR6-induced epithelial-to-mesenchymal transition in gastric cancer via the Akt pathway (not ERK1/2): CCL20 activates p-CrkL, p-ERK1/2, p-Akt, vimentin, N-cadherin and MMP2 in a dose-dependent manner; si-CrkL ablates CCL20-induced vimentin, N-cadherin, MMP2 and migration/invasion, but does not affect p-ERK1/2.\",\n      \"method\": \"siRNA knockdown of CrkL, CCL20 stimulation dose-response, western blot for signaling pathway components, migration/invasion assays\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA dissection of downstream signaling, gain/loss of function, single lab\",\n      \"pmids\": [\"26044596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCL20/MIP-3α accounts for ~40% of RA synovial fluid chemotactic activity for monocytes; in vitro monocyte chemotaxis induced by MIP-3α is inhibited by pertussis toxin pretreatment of monocytes, confirming signaling through a Gi-coupled receptor.\",\n      \"method\": \"Modified Boyden chamber monocyte chemotaxis assay, pertussis toxin inhibition, ELISA, flow cytometry\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional chemotaxis with mechanistic pertussis toxin perturbation, single lab\",\n      \"pmids\": [\"12695561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCR6 selectively promotes monocyte (but not T cell) adhesion to inflamed endothelium and monocyte recruitment in an acute air-pouch inflammatory model; CCR6 reduces circulating Gr-1high and Gr-1low monocytes in Ccr6−/−Ldlr−/− mice, establishing a role for CCR6 in monocyte mobilization, adhesion, and chemotaxis that drives atherosclerosis.\",\n      \"method\": \"Ccr6−/−Ldlr−/− double-KO mice, in vitro monocyte adhesion assay to inflamed endothelium, in vivo air pouch monocyte recruitment model, flow cytometry\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with KO mice, single lab\",\n      \"pmids\": [\"24114205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PF-07054894 is a CCR6 antagonist that binds with slow dissociation kinetics (slower off-rate for CCR6 vs. CCR7/CXCR2) producing insurmountable inhibition of CCL20/CCR6-mediated human T-cell chemotaxis; oral administration in cynomolgus monkeys increases circulating CCR6+ T cells (consistent with blockade of homeostatic tissue egress); the compound also causes upregulation of cell-surface CCR6 in B cells in vivo and in vitro.\",\n      \"method\": \"β-arrestin GPCR panel screen (168 receptors), human T-cell chemotaxis assay, [3H]-PF-07054894 radioligand binding/dissociation kinetics, in vivo primate pharmacology, IL-23 mouse skin model\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — radioligand binding kinetics plus in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"37142443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCR6 in endometriosis: CCR6 binds TFEB in ESCs (co-IP confirmed), inhibiting TFEB nuclear translocation, thereby blocking lysosomal function and autophagic flux (autolysosome degradation), which promotes ESC proliferation and migration; macrophage-derived CCL20 activates this CCR6-TFEB pathway in co-culture.\",\n      \"method\": \"Co-immunoprecipitation (CCR6/TFEB), TFEB nuclear translocation assay, mRFP-GFP-LC3 autophagic flux reporter, lysosome function assays (Lyso-tracker, Gal3, acid phosphatase), CCL20-neutralizing antibody in vivo mouse model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional nuclear translocation and autophagic flux assays, single lab\",\n      \"pmids\": [\"35841069\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCR6 is a Gαi-coupled seven-transmembrane chemokine receptor whose primary ligand CCL20 (and β-defensins as secondary ligands) induces Gαi-mediated signaling (inhibition of cAMP, p130Cas phosphorylation, Akt/mTOR/STAT3 and AKT/NF-κB/VEGF pathway activation), driving directed chemotaxis of immature dendritic cells, Th17 cells, regulatory T cells, B cells, monocytes, and γδ T cells to sites of CCL20 expression at epithelial/mucosal surfaces and sites of inflammation; its cryo-EM structure reveals that CCL20 activates the receptor via a shallow extracellular binding mode that allosterically rearranges a noncanonical toggle switch to open the G protein-coupling crevice, while allosteric small-molecule antagonists occupy either an extracellular pocket disrupting this activation network or an intracellular pocket overlapping the G protein site; beyond chemotaxis, CCR6 signaling regulates osteoblast differentiation and survival via PI3K-AKT, controls iTreg-to-Th17 lineage plasticity, modulates Treg glycolysis and immunosuppressive function, interacts with CatSper to mediate Ca2+ influx and chemotaxis in sperm, and associates with TFEB to block autophagic flux in endometriotic stromal cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCR6 is a Gαi-coupled seven-transmembrane chemokine receptor that directs chemotaxis of immune and epithelial cell populations toward its specific ligand CCL20/LARC, governing mucosal and inflammatory tissue homing [#0, #7]. CCL20 binds CCR6 with nanomolar affinity and selectively triggers calcium flux and directed migration; cryo-EM of the CCL20–CCR6–Gαo complex shows the ligand engaging a shallow extracellular pocket that allosterically rearranges a noncanonical toggle switch to open the intracellular G-protein crevice, a non-deep mode of protein-agonist activation [#0, #24]. Downstream of pertussis-toxin-sensitive Gαi, CCR6 inhibits cAMP production and phosphorylates p130Cas, and through Akt/mTOR/STAT3 and AKT/NF-κB/VEGF signaling shapes cell migration, survival, and lineage decisions [#7, #21, #25]. CCR6 is required for trafficking of myeloid dendritic cells to the Peyer's-patch subepithelial dome and for mucosal IgA immunity, and for recruitment of Th17 cells, IL-10-producing colon-tropic iTregs, B cells, neutrophils, plasmacytoid DCs, monocytes, and γδ T cells to epithelial and inflamed tissues [#2, #5, #9, #11, #13, #15]. Its expression is transcriptionally programmed by RORα/RORγt and PLZF (ZBTB16) in Th17 cells and dynamically tuned by cytokines such as TGF-β, IL-10, IL-4, and IFN-γ [#9, #19, #6]. CCR6 signaling also acts beyond leukocyte trafficking: it promotes osteoblast differentiation and survival via PI3K-AKT [#26], drives CCL20-dependent tumor growth, angiogenesis, EMT, and Treg-mediated immunosuppression across colorectal, ovarian, gastric, and cutaneous T-cell malignancies [#18, #25, #29, #31, #33], mediates CatSper-dependent Ca2+ influx and chemotaxis in sperm [#22], and associates with TFEB to block autophagic flux in endometriotic stromal cells [#37]. High-resolution inactive-state structures define two distinct allosteric antagonist pockets, providing a template for small-molecule CCR6 inhibitors [#30, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the receptor's ligand identity was the foundational question; pairing CCR6 with CCL20 defined its molecular input and selectivity.\",\n      \"evidence\": \"Calcium flux, chemotaxis, and SEAP-fusion saturation binding in stably transfected cells\",\n      \"pmids\": [\"9169459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define downstream G-protein coupling\", \"No structural basis for ligand recognition\", \"Secondary β-defensin ligands not yet identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Whether CCR6 had a non-redundant physiological role was unknown; knockout mice showed it is required for dendritic-cell positioning in the gut subepithelial dome and for mucosal humoral immunity.\",\n      \"evidence\": \"CCR6-knockout mouse immunohistochemistry and oral antigen/rotavirus challenge\",\n      \"pmids\": [\"10843382\", \"11254677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling underlying DC positioning not defined\", \"Did not address other CCR6+ cell types\", \"Systemic vs mucosal compartmentalization mechanism unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining which cell types use CCR6 mapped the breadth of its trafficking program; mature/memory B cells, neutrophils, and myeloid DC subsets were shown to be functionally CCR6-responsive and cytokine-regulated.\",\n      \"evidence\": \"Flow cytometry, transmigration assays, radioligand binding, CCR6-EGFP knock-in reporter, and cytokine stimulation across cell types\",\n      \"pmids\": [\"11001880\", \"11090084\", \"11754009\", \"11698430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reporter does not establish in vivo migratory function for each subset\", \"Cytokine regulation mostly single-lab in vitro\", \"Functional consequence of subset-specific expression varies by context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The receptor's signaling output was undefined; apical CCL20 stimulation of polarized epithelium showed Gαi coupling that inhibits cAMP and phosphorylates p130Cas.\",\n      \"evidence\": \"Polarized intestinal epithelial cell lines, pertussis toxin perturbation, cAMP/chloride secretion and p130Cas phosphorylation readouts\",\n      \"pmids\": [\"15483227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link signaling to specific migratory or transcriptional outputs\", \"Single epithelial-cell context\", \"β-arrestin / desensitization arm not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How CCR6 expression is wired to T-helper identity was unknown; TGF-β with RORα/RORγt was shown to drive CCR6 in Th17 cells, which also make CCL20, creating an autocrine recruitment loop tied to autoimmune disease.\",\n      \"evidence\": \"In vitro Th17 differentiation, nuclear receptor gain/loss, CCR6-deficient mice in EAE, migration assays\",\n      \"pmids\": [\"19050256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription-factor binding at CCR6 locus not shown here\", \"Th17 vs Treg balance not addressed\", \"Human relevance inferred from mouse model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether CCR6 marks distinct regulatory T-cell function was open; CCR6 was shown to define colon-tropic IL-10+ iTregs whose suppressive capacity depends on the receptor.\",\n      \"evidence\": \"T-cell transfer colitis model with CCR6-KO and co-transfer experiments\",\n      \"pmids\": [\"20720211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CCR6 to suppressive function not defined\", \"Single disease model\", \"Whether effect is migration-dependent or intrinsic unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extending CCR6 trafficking beyond lymphocytes, monocyte homeostasis and pDC homing were shown to be CCR6-dependent, implicating the receptor in atherosclerosis and inflamed-tissue surveillance.\",\n      \"evidence\": \"Ccr6−/−ApoE−/− mice, bone marrow chimeras, monocyte chemotaxis, competitive pDC adoptive transfer in skin tumor model\",\n      \"pmids\": [\"21680896\", \"21937703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinguishing monocyte mobilization from local chemotaxis requires further dissection\", \"pDC findings single-lab\", \"Downstream signaling in monocytes/pDCs not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The role of CCR6 in tissue-specific inflammatory positioning was clarified across liver, eye, and vascular contexts, including a protective γδ T-cell axis driving HSC apoptosis via Fas-ligand.\",\n      \"evidence\": \"CCR6-KO mice in liver fibrosis and dry eye models, adoptive transfer epistasis, antibody blockade, monocyte adhesion assays\",\n      \"pmids\": [\"23959575\", \"23702781\", \"24114205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-contact apoptosis mechanism downstream of recruitment, not receptor signaling\", \"Some readouts antibody-blockade only\", \"Context-dependent pro- vs anti-inflammatory roles unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Direct transcriptional control of CCR6 was established; PLZF (ZBTB16) binds upstream enhancer elements and is required for CCR6 and Th17 gene expression, cross-regulating RORγt.\",\n      \"evidence\": \"ChIP for PLZF/p300/histone marks and ZBTB16 siRNA knockdown in human Th17 cells\",\n      \"pmids\": [\"25833398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test CCR6 enhancer activity in reporter assays\", \"Mechanism of PLZF-RORγt cross-regulation incomplete\", \"Single-lab human T-cell system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CCR6 function beyond immune trafficking emerged; it drives osteoblast differentiation/survival via PI3K-AKT and promotes tumor angiogenesis through AKT/NF-κB/VEGF-A.\",\n      \"evidence\": \"Ccr6−/− and Ccl20−/− mice with µCT/histomorphometry, osteoblast differentiation and AKT assays, CRC cell knockdown/overexpression with HUVEC angiogenesis assays\",\n      \"pmids\": [\"26890063\", \"29097259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-intrinsic osteoblast vs immune-mediated bone effect not fully separated\", \"Angiogenesis findings single-lab\", \"Whether bone role uses canonical Gαi chemotaxis machinery unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"How CCR6 signaling shapes Treg/Th17 plasticity was addressed; CCL20-CCR6 inhibits iTreg suppressor function and drives Treg-to-Th17 conversion via Akt/mTOR/STAT3.\",\n      \"evidence\": \"In vitro Treg differentiation/suppression assays with CCR6 blockade and phospho-western blots\",\n      \"pmids\": [\"29126851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only\", \"In vivo relevance of lineage conversion not shown here\", \"STAT3/mTOR causality not tested by pathway inhibition\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A non-canonical CCR6 role in sperm was defined; CCR6 physically interacts with CatSper to mediate ligand-induced Ca2+ influx required for motility, hyperactivation, and acrosome reaction.\",\n      \"evidence\": \"Co-IP, co-localization, siRNA knockdown, Ca2+ current and sperm functional assays in human sperm\",\n      \"pmids\": [\"29207656\", \"23765988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry/structural basis of CCR6-CatSper interaction unknown\", \"Single Co-IP without reciprocal structural validation\", \"Whether Gαi signaling participates unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether CCR6 itself is somatically altered in cancer was tested; truncating mutations cluster in the C-terminal tail in MALT lymphoma, predicted to abolish β-arrestin-mediated desensitization.\",\n      \"evidence\": \"Whole exome sequencing of MALT lymphoma with bioinformatic clustering analysis\",\n      \"pmids\": [\"29674500\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence inferred but not experimentally validated\", \"Constitutive signaling not demonstrated\", \"No β-arrestin recruitment assay performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The structural basis of CCR6 activation was resolved; cryo-EM showed CCL20 binds a shallow extracellular pocket and allosterically opens the G-protein crevice without deep 7-TM engagement.\",\n      \"evidence\": \"3.3 Å cryo-EM of CCL20–CCR6–engineered Gαo complex\",\n      \"pmids\": [\"32541785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"β-defensin secondary-ligand binding mode not resolved\", \"Dynamics of toggle-switch rearrangement static-structure inferred\", \"Did not capture inactive/antagonist states\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CCR6 was placed downstream of epithelial tumor-suppressor loss and as an amplifier of inflammatory cross-talk; deleting Ccr6 abrogated immune recruitment in SMAD4-loss carcinogenesis and broke an IL-6/CCL20 dermatitis loop.\",\n      \"evidence\": \"Conditional Smad4-KO × Ccr6-KO epistasis with tumor quantification, and Ccr6/IL-6 KO crosses with scRNA-seq in radiation dermatitis\",\n      \"pmids\": [\"35863523\", \"35785521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which CCR6+ cell type is the dominant effector not fully resolved\", \"Cross-talk loop mechanism partly correlative\", \"Translation to human disease inferred\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A receptor-scaffold mechanism beyond chemotaxis was found; CCR6 binds TFEB and blocks its nuclear translocation, inhibiting autophagic flux to promote endometriotic stromal cell proliferation.\",\n      \"evidence\": \"Co-IP of CCR6/TFEB, TFEB translocation and mRFP-GFP-LC3 autophagic flux assays, CCL20-neutralizing antibody mouse model\",\n      \"pmids\": [\"35841069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect CCR6-TFEB binding not distinguished\", \"Single Co-IP context\", \"Relationship to canonical Gαi signaling unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The inactive-state pharmacology and metabolic immunosuppressive role were defined; two allosteric antagonist pockets were structurally mapped, and CCR6 was shown to drive Treg glycolysis required for CD8 suppression and immunotherapy resistance.\",\n      \"evidence\": \"Cryo-EM of inactive CCR6 with OXM and SQA1 antagonists; Ccr6-KO mice in multiple tumor models with metabolic and anti-PD-1 assays; antagonist binding-kinetics studies\",\n      \"pmids\": [\"39217154\", \"39133127\", \"37142443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Minimal cooperativity between pockets limits dual-targeting strategy clarity\", \"Metabolic mechanism single-lab\", \"Antagonist efficacy in human disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCR6's diverse non-chemotactic functions (osteoblast survival, CatSper coupling, TFEB sequestration) mechanistically relate to its canonical Gαi-chemotaxis machinery, and whether they share or diverge from the structurally defined activation network, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified signaling model linking scaffold and chemotactic roles\", \"β-arrestin/desensitization regulation not experimentally characterized in disease mutants\", \"Cell-type-specific effector wiring undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 24]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 17, 22, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 24, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 13, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CCL20\",\n      \"CATSPER1\",\n      \"TFEB\",\n      \"CRKL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}