Affinage

CCR9

C-C chemokine receptor type 9 · UniProt P51686

Length
369 aa
Mass
42.0 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCR9 is a Gi-protein-coupled chemokine receptor that exclusively binds CCL25/TECK to direct the migration and homing of T cells, B cells, IgA+ plasma cells, and plasmacytoid dendritic cells to the thymus and small intestine, thereby orchestrating lymphocyte development, mucosal immunity, and oral tolerance. CCR9 signals through pertussis toxin-sensitive Gi proteins, activating PI3K/AKT and p38/ERK cascades that regulate chemotaxis, cell survival, integrin-mediated adhesion, and MMP expression (PMID:11046037, PMID:20127861, PMID:33347617). CCR9 cooperates with CCR7 to recruit hematopoietic progenitors to the thymus during both fetal and adult T lymphopoiesis, and its expression is transcriptionally induced by pre-TCR signaling and by a cooperative RAR/RXR–NFATc2 mechanism downstream of retinoic acid (PMID:16809609, PMID:19965655, PMID:21148038). The crystal structure of CCR9 bound to the clinical antagonist vercirnon revealed a novel intracellular allosteric site that blocks G-protein coupling, and CCR9 additionally forms a functional heteromeric complex with dopamine receptor D5 that confers colonic tropism to effector T cells during intestinal inflammation (PMID:27926729, PMID:33864900).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Identification of CCR9 as the exclusive receptor for CCL25/TECK resolved which receptor mediates thymocyte and gut lymphocyte chemotaxis, establishing the founding axis for mucosal immunology studies.

    Evidence Transfectant chemotaxis, calcium flux in HEK293 and primary thymocytes, mAb blocking, independently replicated in three concurrent papers

    PMID:10229797 PMID:10498628 PMID:10544196

    Open questions at the time
    • Downstream signaling pathways not yet defined
    • In vivo requirement not yet tested via gene targeting
  2. 2000 High

    Establishing that CCR9 couples to Gi proteins and that pre-TCR signaling induces CCR9 expression defined the receptor's signal transduction mechanism and developmental regulation in thymocytes.

    Evidence Pertussis toxin sensitivity of chemotaxis in small bowel lymphocytes; CCR9 mRNA induction in Rag2−/− mice after anti-CD3 stimulation

    PMID:10602049 PMID:10623805 PMID:11046037

    Open questions at the time
    • Specific G-protein subtypes not identified
    • Transcription factor binding to the CCR9 promoter unknown
  3. 2001 High

    CCR9 knockout mice demonstrated that CCR9 is the sole functional TECK receptor on thymocytes and is required for normal thymic seeding, γδ IEL development, and bone marrow B cell homeostasis.

    Evidence CCR9−/− mice generated by homologous recombination; chemotaxis abolished; competitive BM transplantation showing reduced thymic repopulation

    PMID:11675330 PMID:11884450

    Open questions at the time
    • Redundancy with CCR7 in thymic progenitor seeding not yet assessed
    • IgA plasma cell homing role not yet tested
  4. 2004 High

    Multiple in vivo studies revealed that CCR9 directs IgA+ plasma cell and T cell homing to the small intestinal lamina propria and regulates CD103 integrin induction on IELs, broadening CCR9's role beyond thymocyte biology to mucosal effector function.

    Evidence CCR9−/− adoptive transfers showing defective IgA+ PC migration; CCR9−/− CD8 T cells with delayed CD103 induction; CCL25-induced E-cadherin adhesion blocked by pertussis toxin

    PMID:14744993 PMID:15368288

    Open questions at the time
    • Mechanism linking CCR9 signaling to CD103 upregulation not defined
    • Colonic vs small intestinal specificity not explained
  5. 2004 Medium

    Discovery that CCR9 on melanoma and prostate cancer cells mediates CCL25-directed migration, invasion, and MMP induction established an oncological dimension for the CCR9/CCL25 axis.

    Evidence In vitro migration/invasion assays, mAb blocking, RT-PCR of MMP panel in cancer cell lines and primary melanoma cells

    PMID:15086554 PMID:15623660

    Open questions at the time
    • In vivo metastasis models not yet performed at this time
    • Signaling pathway downstream of CCR9 in cancer cells unknown
  6. 2006 High

    CCR7–CCR9 double knockout studies showed these two receptors cooperate to guide fetal thymic colonization, and forced CCR9 expression on immature thymocytes demonstrated that tightly regulated CCR9 expression is essential for proper intrathymic positioning.

    Evidence CCR7−/−CCR9−/− double KO embryological analysis; CCR9 transgenic mice with DN-stage developmental block and cortical mislocalization

    PMID:16365398 PMID:16809609

    Open questions at the time
    • Whether CCR9/CCR7 cooperation involves co-signaling or sequential chemokine gradients undetermined
    • Signals that downregulate CCR9 at DN stage not identified
  7. 2007 High

    CCR9 was shown to be required for plasmacytoid DC homing to the small intestine and to regulate multiple stages of adult T lymphopoiesis beyond initial thymic seeding, revealing broader immune cell trafficking functions.

    Evidence CCR9−/− mice lacking intestinal pDCs; competitive transfers showing CCR9−/− HSC deficiency in generating thymocyte subsets including DP-to-SP transition

    PMID:17404233 PMID:17911179

    Open questions at the time
    • Mechanism by which CCR9 facilitates TCR-MHC conjugate formation unclear
    • Whether pDC homing defect affects tolerance induction not yet tested
  8. 2009 High

    CCR7–CCR9 double deficiency in adult mice confirmed near-complete blockade of thymic progenitor settling, and HTLV-1 Tax was identified as a transcriptional activator of CCR9, linking viral pathogenesis to gut tropism of ATL cells.

    Evidence CCR7−/−CCR9−/− competitive transfers; Tax-inducible system with CCR9 promoter-luciferase reporter

    PMID:17205512 PMID:19965655

    Open questions at the time
    • Tax-responsive element in CCR9 promoter not mapped
    • Whether Tax-induced CCR9 is sufficient for GI infiltration in vivo untested
  9. 2010 High

    The transcriptional mechanism for retinoic acid-induced CCR9 expression was defined: NFATc2 cooperates with RAR/RXR at the Ccr9 promoter, with RXR agonists enhancing RA-dependent gut homing, establishing the molecular basis of vitamin A-dependent mucosal immunity.

    Evidence Promoter reporter mutagenesis, DNA-affinity precipitation, co-immunoprecipitation of NFATc2–RARα/RXRα, in vivo homing with RXR agonists

    PMID:20881191 PMID:21148038

    Open questions at the time
    • Chromatin-level regulation (histone modifications, enhancers) not examined
    • Whether this mechanism operates equivalently in DCs and B cells unknown
  10. 2010 Medium

    PI3K/AKT was identified as the critical downstream effector of CCR9-mediated antiapoptotic and pro-invasive signaling in cancer cells, with wortmannin abolishing CCL25-driven survival and mAb neutralization reducing tumor burden in vivo.

    Evidence PI3K inhibitor (wortmannin) in prostate cancer cells, anti-CCR9 mAb in xenograft model, Western blot for AKT/ERK/GSK-3β/caspase-3

    PMID:20127861

    Open questions at the time
    • Whether PI3K/AKT is the dominant pathway in all CCR9-expressing cancers not established
    • Direct biochemical link between Gi and PI3K activation not shown
  11. 2011 High

    CCR9 was established as essential for oral immune tolerance: CCR9−/− mice fail to develop oral tolerance, and the mechanism requires CCR9-dependent gut homing of Foxp3+ IL-10-producing Tregs, bridging mucosal homing to immune regulation.

    Evidence CCR9−/− and β7−/− KO mice, adoptive transfer rescue, DEREG Treg depletion, DTH and EAE tolerance models

    PMID:21300065 PMID:21925467

    Open questions at the time
    • Whether CCR9 directly signals in Tregs to enhance suppressive function or merely directs their migration is unclear
    • Role of CCR9+ DCs in Treg induction during oral tolerance not dissected
  12. 2016 High

    The 2.8 Å crystal structure of CCR9 with vercirnon revealed a novel intracellular allosteric binding site (IABS) that blocks G-protein coupling, providing a structural framework for drug design against chemokine receptors.

    Evidence X-ray crystallography at 2.8 Å resolution

    PMID:27926729

    Open questions at the time
    • Structure of CCR9 in active, G-protein-bound state not determined
    • Conformational dynamics of allosteric inhibition not captured by static crystal structure
  13. 2021 High

    Discovery that CCR9 forms a functional heteromeric complex with dopamine receptor D5 explained how colonic tropism of CD4+ effector T cells is achieved during gut inflammation, since CCR9 alone confers only small intestinal specificity.

    Evidence BRET, bimolecular fluorescence complementation, proximity ligation assay, T cell transfer colitis model

    PMID:33864900

    Open questions at the time
    • Stoichiometry and structure of the CCR9:DRD5 heteromer unknown
    • Downstream signaling unique to the heteromer not characterized
    • Whether other GPCR heteromers with CCR9 exist is unexplored
  14. 2022 Medium

    PROTAC-based degradation of CCR9 via the intracellular allosteric site demonstrated that the IABS can be exploited for targeted protein degradation, opening new pharmacological strategies beyond conventional antagonism.

    Evidence PROTAC degradation assay, NanoBRET binding kinetics with fluorescent IABS ligand

    PMID:34936714

    Open questions at the time
    • In vivo efficacy of CCR9-PROTACs not demonstrated
    • Selectivity of degradation across GPCR family not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the active-state structure of CCR9 with Gi, the signaling logic of the CCR9:DRD5 heteromer, whether CCR9 directly influences Treg suppressive programs beyond homing, and the therapeutic potential of intracellular allosteric antagonists or PROTACs in inflammatory bowel disease and cancer.
  • Active-state CCR9–Gi complex structure not solved
  • CCR9:DRD5 heteromer signaling cascade and structural basis unknown
  • No clinical validation of PROTAC or next-generation IABS antagonists

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 7 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4
Partners
CCL25DRD5EZRNFATC2RARARXRA
Complex memberships
CCR9:DRD5 heteromer

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 GPR-9-6 (renamed CCR9) was identified as the principal chemokine receptor for TECK (CCL25): CCL25 mediates chemotaxis of GPR-9-6/L1.2 transfectants, and this activity is blocked by anti-GPR-9-6 monoclonal antibody 3C3. CCR9 is selectively expressed on intestinal homing alpha4beta7(high) T lymphocytes, all intestinal lamina propria and intraepithelial lymphocytes, and the majority of thymocytes, but not on CLA+ skin-homing T cells, NK cells, monocytes, or granulocytes. Transfectant chemotaxis assay, mAb blocking, flow cytometry, RT-PCR The Journal of experimental medicine High 10544196
1999 GPR-9-6 (CCR9) was identified as a specific receptor for TECK: human and murine TECK induced intracytoplasmic calcium mobilization in HEK 293/GPR-9-6 transfectants, and human TECK induced in vitro migration of HEK 293/human GPR-9-6 cells. Calcium flux assay, transfectant chemotaxis assay Journal of immunology (Baltimore, Md. : 1950) High 10229797
1999 TECK (CCL25) specifically induced calcium flux in CCR9-expressing cell lines and efficaciously induced chemotaxis of immature CD4+CD8+ double-positive and mature CD4+ and CD8+ single-positive human thymocytes. Calcium flux assay, chemotaxis assay with primary human thymocytes Blood High 10498628
2000 CCR9 expression is strongly induced by pre-TCR signaling during thymocyte development: GPR-9-6/CCR9 mRNA is induced as thymocytes undergo the double-negative to double-positive transition following anti-CD3 treatment of Rag2-/- mice. TECK, produced by thymic medullary dendritic cells, induces calcium flux and chemotaxis of CCR9-transfected cells and stimulates migration of double-positive thymocytes. RT-PCR, calcium flux assay, chemotaxis assay, in vivo pre-TCR signaling model (Rag2-/- + anti-CD3) Journal of immunology (Baltimore, Md. : 1950) High 10623805
2000 Thymic epithelial cells (not dendritic cells) are the predominant source of TECK/CCL25 in the thymus. CCR9 is highly expressed by double-positive thymocytes and TECK can chemoattract both double-positive and single-positive thymocytes. The CCR9 gene was localized to mouse chromosome 9F1-F4. cDNA cloning, RT-PCR, chemotaxis assay, immunohistochemistry, chromosomal mapping European journal of immunology High 10602049
2000 CCR9-mediated TECK/CCL25-induced chemotaxis of small bowel lamina propria mononuclear cells is sensitive to pertussis toxin (indicating Gi-protein coupling) and partially inhibited by antibodies to CCR9. CCR9 is selectively expressed on small bowel but not colonic lamina propria lymphocytes. Pertussis toxin inhibition, mAb blocking, chemotaxis assay, flow cytometry Journal of immunology (Baltimore, Md. : 1950) High 11046037
2001 CCR9 is the sole physiological receptor for TECK/CCL25 on thymocytes: thymocytes from CCR9-/- mice fail to respond to TECK/CCL25 in chemotaxis assays. CCR9 deletion reduces TCRgammadelta+ intraepithelial lymphocytes in the small intestine and reduces bone marrow pre-pro-B cells. CCR9(-/-) bone marrow is less efficient at repopulating the thymus in competitive transplantation. CCR9 gene knockout (homologous recombination), chemotaxis assay, competitive transplantation, flow cytometry Blood / Journal of immunology High 11675330 11884450
2002 CCR9/CCL25 is required for the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes: expression of a CCL25-intrakine gene (blocking CCL25 response) in bone marrow-derived c-kit+ cells dramatically reduced cryptopatch numbers and IEL in the small intestine, while thymic, splenic and lymph node T cells developed normally. CD11c+ dendritic stromal cells in cryptopatches expressed CCL25 and c-kit+ Lin- BM cells expressed CCR9 and showed vigorous chemotactic response to CCL25. Intrakine gene expression (CCL25-intrakine in BM reconstitution), RT-PCR, chemotaxis assay, immunohistochemistry International immunology High 12096027
2004 CCR9 is required for IgA+ plasma cell localization to the small intestinal lamina propria: CCR9-deficient IgA+ plasma cells are substantially reduced in the lamina propria; CCR9-/- IgA+ PCs show reduced migration into the small intestine in adoptive transfer experiments; CCR9 mutants fail to mount a normal IgA response to an orally administered antigen. IgA+ PCs express high CCR9 levels in mesenteric lymph node and Peyer's patches but downregulate it once in the small intestine. CCR9 KO mouse, adoptive transfer, flow cytometry (new anti-murine CCR9 mAb), ELISA The Journal of experimental medicine High 14744993
2004 Functionally active CCR9 on melanoma cells (but only on those from small intestinal metastases) mediates migration and invasion toward CCL25. Only cells from small intestinal metastases showed CCR9-dependent receptor downregulation and actin polymerization in response to CCL25, while CCR9-expressing cells from other sites did not respond. Flow cytometry, RT-PCR, receptor downregulation assay, actin polymerization assay The Journal of investigative dermatology Medium 15086554
2004 CCL25/CCR9 promotes induction and function of CD103 on intestinal CD8+ intraepithelial lymphocytes: CCR9-/- CD8+ T cells show significant delay in CD103 induction upon entry into the small intestinal epithelium. CCL25 induces transient, dose-dependent, pertussis toxin-sensitive CD103-mediated adhesion of CD8+ IEL to murine E-cadherin-Fc fusion protein. CCR9 KO mouse, in vivo T cell tracking, adhesion assay with E-cadherin-Fc, pertussis toxin inhibition European journal of immunology High 15368288
2004 CCR9/CCL25 mediates recruitment of gut-derived CCR9+ T cells to the liver in primary sclerosing cholangitis via aberrant expression of CCL25 on hepatic endothelium, which activates alpha4beta7 binding to MAdCAM-1. Immunohistochemistry, flow cytometry, in vitro adhesion assay The Journal of experimental medicine Medium 15557349
2004 CCR9-CCL25 interaction promotes prostate cancer cell migration and invasion and modulates expression of MMP-1, MMP-10, MMP-11, MMP-13, and MMP-2, but not other MMPs. Neutralization of CCL25-CCR9 interaction impaired migration and invasion of LNCaP and PC3 cell lines. In vitro migration/invasion chamber assay, mAb blocking, flow cytometry, RT-PCR Clinical cancer research Medium 15623660
2006 CCR9 expression on thymocytes is not induced until the DN3 stage; CCR9 expression is influenced by pre-TCR signals and dramatically up-regulated in a transitional population between DN4 and double-positive stages. In the periphery, functional CCR9 is expressed by all naive CD8 T cells but not by naive CD4 T cells — the first observed difference in homing receptor expression between naive lymphocyte populations. Flow cytometry, CCR9-/- mouse, RT-PCR, chemotaxis assay at multiple developmental checkpoints European journal of immunology High 16342233
2006 CCR7 and CCR9 cooperate to guide fetal thymus colonization before (but not after) vascularization: mice doubly deficient for CCR7 and CCR9 are specifically defective in prevascular fetal thymus colonization, with selective loss of the first wave of T cell development (epidermal Vgamma3+ gammadelta T cells). CCL21 (CCR7 ligand) is expressed by parathyroid primordium and CCL25 (CCR9 ligand) by Foxn1-dependent thymic primordium, revealing coordinated chemokine guidance from adjacent primordia. Double KO mouse genetics, embryological analysis, in situ hybridization, flow cytometry Blood High 16809609
2006 Forced premature expression of CCR9 on immature DN thymocytes (CCR9 transgenic mice) causes a partial developmental block at the DN stage, marked reduction in double-positive and single-positive thymocytes, and scattering of CD25high DN cells throughout the cortex rather than confinement to the subcapsular region. Down-regulation of CCR9 is not essential for thymocyte emigration. CCR9 transgenic mouse, immunohistochemistry, flow cytometry, thymic export assay Journal of immunology (Baltimore, Md. : 1950) High 16365398
2007 CCR9 is required for homing of plasmacytoid dendritic cells (pDC) to the small intestine: CCR9-deficient animals lack pDCs in the intestine but not in lung, liver, or secondary lymphoid organs. Competitive adoptive transfers reveal CCR9-/- pDCs are impaired in homing to the small intestine. In cholera toxin-induced gut inflammation, pDCs are recruited to the intestine in WT but not CCR9-/- animals. Intestinal pDCs are required for rapid mobilization of lamina propria myeloid DCs after oral TLR7/8 ligand challenge. CCR9 KO mouse, competitive adoptive transfer, flow cytometry, inflammation model, pDC rescue experiment Proceedings of the National Academy of Sciences of the United States of America High 17404233
2007 CCR9 is involved at multiple stages of adult T lymphopoiesis: CCR9-/- hematopoietic stem cells are deficient in generating all major thymocyte subsets including DN1 cells in competitive transfers. Early thymic progenitor and DN2 numbers are reduced in adult CCR9-/- thymus. CCR9-/- DN cells are outcompeted in generating DP thymocytes after intrathymic injection. CCR9-/- preselection DP thymocytes are disadvantaged in generating CD4 SP thymocytes, correlating with reduced ability to form TCR-MHC-dependent conjugates with thymic epithelial cells. Competitive bone marrow transfers, fetal thymic organ cultures, intrathymic injection, reaggregation thymic organ cultures, flow cytometry Journal of leukocyte biology High 17911179
2008 CCR9+ plasmacytoid DCs constitute a tolerogenic DC subset that migrates to CCL25, has an immature phenotype, rapidly downregulates CCR9 upon maturation-inducing pDC-restricted TLR ligands, potently induces regulatory T cell function, and suppresses antigen-specific immune responses including acute graft-versus-host disease. Flow cytometry, CCR9+ pDC isolation, in vitro Treg induction, in vivo GVHD model, TLR ligand maturation assay Nature immunology High 18836452
2008 CCR9-CCL25 axis mediates preferential metastasis of cutaneous melanoma to the small intestine: CCR9+ melanoma cells from small intestinal metastases migrate and invade in response to CCL25, and this is inhibited by anti-CCR9 antibody or siRNA knockdown of CCR9. CCR9+ melanoma cells also co-express alpha4beta1 integrin. In vitro migration/invasion assay, siRNA knockdown, mAb blocking, flow cytometry, RT-PCR, IHC Clinical cancer research High 18245522
2009 CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus: CCR7-/-CCR9-/- double knockout progenitors are almost completely restricted from thymic settling in competitive assays, and CCR7-/-CCR9-/- mice have severe reductions in early thymic progenitors. CCR7 sustains thymic settling in the absence of CCR9. Compensatory intrathymic expansion partially recovers thymic cellularity. Double KO mouse genetics, competitive adoptive transfer, flow cytometry Blood High 19965655
2010 Retinoic acid (RA) induces CCR9 expression on T cells through cooperativity between NFATc2 and the RAR/RXR complex: NFATc2 binds two NFAT-binding sites in the Ccr9 promoter, RAR/RXR binds an RA response element half-site, and NFATc2 directly interacts with RARα and RXRα to enhance RARα binding. NFATc1 also binds these sites but inhibits NFATc2-dependent promoter activity. Transient TCR stimulation (6-24h) is required for RA responsiveness. Reporter assay, DNA-affinity precipitation, co-immunoprecipitation (NFATc2–RARα/RXRα), cyclosporin A treatment, promoter mutagenesis Journal of immunology (Baltimore, Md. : 1950) High 21148038
2010 RXR activation cooperates with RAR activation to efficiently induce CCR9 on T cells and enhance gut homing: RXR agonist (PA024) or organotin RXR-binding compounds markedly enhanced all-trans-RA/RAR agonist-induced CCR9 surface expression on naive CD4+ T cells, and CD4+ T cells treated with all-trans-RA plus tributyltin migrated into the small intestine much more efficiently upon adoptive transfer. Flow cytometry, adoptive transfer, RAR/RXR agonist/antagonist pharmacology, in vivo intestinal homing assay Journal of immunology (Baltimore, Md. : 1950) High 20881191
2010 IL-4 acts on mesenteric lymph node dendritic cells via IL-4Rα signaling to induce CCR9 imprinting on CD4+ T cells, by upregulating retinaldehyde dehydrogenase 2 (RALDH2) mRNA in MLN-DCs and thereby increasing retinoic acid production. Blocking the RA receptor with LE135 abrogated the IL-4-driven CCR9 induction. Co-culture assays, IL-4Ralpha-/- mice, RALDH2 RT-PCR, RAR antagonist (LE135), adoptive transfer Journal of immunology (Baltimore, Md. : 1950) High 18453568
2010 CCR9-CCL25 interaction mediates PI3K/AKT-dependent antiapoptotic signaling in prostate cancer cells: CCL25 upregulates PI3K, AKT, ERK1/2, and GSK-3beta while suppressing caspase-3 activation. A PI3K inhibitor (wortmannin) abolishes these effects. Blocking CCR9-CCL25 interactions with anti-CCR9 mAb or CCL25-neutralizing antibodies restores etoposide-induced cytotoxicity in vitro and reduces tumor burden in vivo. In vitro apoptosis assays, PI3K inhibitor (wortmannin), mAb neutralization, in vivo mouse tumor model International journal of cancer Medium 20127861
2010 CCR9 inhibition by RNA interference in hematopoietic progenitors of apoE-deficient mice significantly retarded atherosclerosis development. CCL25/CCR9-expressing immune cells accumulate in atherosclerotic aortic plaques, and captopril (ACE inhibitor) treatment down-regulates CCR9 and CCL25 in atherosclerotic lesions. RNAi knockdown in vivo, microarray, immunohistology, apoE-/- mouse atherosclerosis model The Journal of biological chemistry Medium 20504763
2011 CCL25-CCR9 interactions promote breast cancer cell migration, invasion, and expression of MMP-1, MMP-9, MMP-11, and MMP-13 in a CCR9-dependent fashion. CCR9-CCL25 axis provides survival advantage to breast cancer cells and inhibits cisplatin-induced apoptosis via PI3K/AKT-dependent (and FAK-independent) pathway activating GSK-3beta and FKHR. Migration/invasion chamber assays, mAb neutralization, FACE assay for PI3K/AKT, FAK inhibitor, apoptosis assays International journal of oncology / World journal of surgical oncology Medium 21344163 21539750
2011 Gut-tropic T cells expressing integrin alpha4beta7 and CCR9 are necessary and sufficient for induction of oral immune tolerance. CCR9-/- and beta7-/- mice cannot be orally tolerized; OT is restored by adoptive transfer of wild-type T cells but not CCR9-/- or beta7-/- T cells. Gut homing of IL-10-producing Foxp3+ Tregs (which require CCR9) is required for oral tolerance induction. CCR9-/- and beta7-/- KO mice, adoptive transfer, delayed-type hypersensitivity and EAE models, MAdCAM-1 blockade, Treg depletion (DEREG mice), IL-10-/- mice Gastroenterology High 21925467
2011 CCR9 on CD8+ T cells mediates migration of regulatory T cells to the intestine in chronic ileitis, suppressing inflammation: CCR9-/- TNFARE mice develop exacerbated ileitis with deficiency of CD4+/CD25+/FoxP3+ and CD8+/CD103+ Tregs in lamina propria and mesenteric lymph nodes. CD8+/CCR9+ cells suppress proliferation of CD4+ T cells in vitro. Anti-CCR9 mAb treatment exacerbated ileitis in vivo. TNFARE KO mouse cross, flow cytometry, in vitro suppression assay, mAb neutralization in vivo Gastroenterology High 21300065
2011 CCR9+ macrophages (CCR9+CD11b+CD11c-) are required for acute liver inflammation: they accumulate in concanavalin A-injured livers, produce TNF-alpha, and induce naive CD4+ T cells to become Th1 cells in vivo and in vitro. CCR9-/- mice do not develop hepatitis unless reconstituted with CCR9+ macrophages from con A-treated mice. Neutralizing antibodies to CCL25 reduce hepatitis induction by blocking CCR9+ macrophage migration and TNF-alpha production. CCR9-/- mice, adoptive transfer of CCR9+ macrophages, CCL25 neutralizing antibody, in vitro Th1 induction assay, flow cytometry Gastroenterology High 22079594
2012 CCR9- pDC-like cells from bone marrow are common DC precursors (with both pDC and cDC potential), whereas CCR9+ pDCs are terminally differentiated. The fate of CCR9- pDC-like precursors depends on the tissue they enter: in BM and liver they differentiate into CCR9+ pDCs, whereas in peripheral lymphoid organs, lung, and intestine they additionally give rise to cDCs. Adoptive transfer of sorted CCR9- vs CCR9+ pDC populations, flow cytometry, OP9-DL1 culture, in vivo fate mapping Blood High 22547585
2016 Crystal structure of CCR9 at 2.8 Å resolution in complex with the antagonist vercirnon reveals that vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism by preventing G-protein coupling. This defines a novel intracellular allosteric binding site on a chemokine GPCR. X-ray crystallography at 2.8 Å resolution Nature High 27926729
2015 CCR9 signaling activates beta-catenin in pancreatic cancer cells, enhancing cell proliferation, invasion, and drug resistance. CCR9-mediated beta-catenin activation is blocked by PI3K/AKT pathway inhibition but not by Wnt antagonism. CCR9/CCL25 increases the lethal dose of gemcitabine. In vitro invasion/proliferation assays, PI3K inhibitor, Wnt antagonist, beta-catenin reporter, drug sensitivity assays Molecular oncology Medium 26003048
2015 CCR9 inhibits Foxp3+ regulatory T cell development: CCR9-/- mice demonstrate higher levels of Foxp3+ Tregs, and CCL25 ligation of CCR9 inhibits Treg cell differentiation in vitro. CCR9-/- mice, in vitro Treg differentiation assay with CCL25 stimulation, flow cytometry PloS one Medium 26230654
2019 CCL25/CCR9 signaling in DCs (specifically CD11b-CD103+ DCs) drives differentiation of Foxp3+ Tregs via intrinsic DC signaling. CCL25-stimulated CCR9+ DCs produce TSLP (not IL-10) to promote Treg differentiation. Adoptive transfer of CCR9+ DCs in vivo promotes Tregs, reduces Th17 cells in GALT, and suppresses OVA-specific gut allergic responses. In vitro Treg differentiation assay, CCR9+ DC adoptive transfer, DSS colitis model, flow cytometry, TSLP/IL-10 neutralization European journal of immunology Medium 31755547
2021 CCR9 forms a heteromeric complex with dopamine receptor D5 (DRD5), and it is this CCR9:DRD5 heteroreceptor complex (not CCR9 alone) that provides colonic tropism to effector CD4+ T cells during gut inflammation. The heteromeric complex is upregulated in intestinal mucosa of IBD patients and behaves differently in signaling than individual receptors. Disruption of CCR9:DRD5 assembly attenuates CD4+ T cell recruitment to the colonic mucosa. BRET (bioluminescence resonance energy transfer), bimolecular fluorescence complementation, in situ proximity ligation assay, adoptive transfer, flow cytometry, T cell transfer colitis model Cellular and molecular gastroenterology and hepatology High 33864900
2021 CCL25/CCR9 axis promotes rheumatoid arthritis FLS and monocyte migration via p38 and ERK phosphorylation. CCL25 polarizes RA monocytes into non-traditional M1 macrophages producing IL-8 and CCL2 through p38 and ERK cascades. CCL25 induces osteoclastogenesis via RANK, cathepsin K, and TNF-alpha (but not RANKL), promoting pannus formation. In vitro migration assay, p38/ERK inhibitors, flow cytometry, osteoclast differentiation assay, ELISA European journal of immunology Medium 33347617
2022 The intracellular allosteric binding site (IABS) of CCR9 identified by the vercirnon crystal structure can be targeted by PROTAC technology to induce CCR9 protein degradation: a CCR9-PROTAC based on vercirnon reduced CCR9 protein levels in cells. A fluorescent ligand for the IABS enabled NanoBRET equilibrium/kinetic binding studies and identified a 4-aminopyrimidine analogue as a new intracellular CCR9 antagonist with improved affinity. PROTAC degradation assay, NanoBRET binding assay, fluorescence microscopy, cell-based and membrane binding assays Angewandte Chemie (International ed. in English) Medium 34936714
2009 HTLV-1 Tax transcriptional activator induces CCR9 expression in ATL cells: Tax induction by Cd2+ in JPX-9 cells upregulates CCR9, and a CCR9 promoter-luciferase reporter is activated by Tax co-transfection or in Cd2+-treated JPX-9 cells. ATL cells infiltrating the gastrointestinal tract are frequently CCR9+. Luciferase reporter assay, Cd2+-inducible Tax system, RT-PCR, immunohistochemistry International journal of cancer Medium 17205512
2009 Ezrin is a key downstream effector of CCL25/CCR9 signaling in T-ALL (MOLT4) cells: CCL25 stimulation induces pseudopodium formation and ERM protein translocation from cytoplasm to cell membrane; ezrin silencing by miRNA inhibits CCL25-induced polarization and invasive behavior of MOLT4 cells. miRNA-mediated ezrin knockdown, morphological imaging, ERM translocation assay Leukemia research Medium 20036004
1999 CCR9 (human CC chemokine receptor gene cluster) was mapped to the 3p21.3 region of the human genome, outside the main CCR cluster but in the broader region between that cluster and the 3p telomere. Radiation hybrid mapping, BAC contig fluorescence hybridization on combed genomic DNA Cytogenetics and cell genetics Medium 10702689

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. The Journal of experimental medicine 367 10544196
2020 CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. International journal of molecular sciences 301 33076281
2000 The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. European journal of immunology 292 10602049
2000 The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. Journal of immunology (Baltimore, Md. : 1950) 259 11046037
2008 CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nature immunology 253 18836452
2004 Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. The Journal of experimental medicine 251 15557349
2002 A role for CCR9 in T lymphocyte development and migration. Journal of immunology (Baltimore, Md. : 1950) 248 11884450
2001 Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 235 11675330
2009 CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 207 19965655
2016 Intracellular allosteric antagonism of the CCR9 receptor. Nature 200 27926729
2007 CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proceedings of the National Academy of Sciences of the United States of America 194 17404233
2004 Chemokine receptor CCR9 contributes to the localization of plasma cells to the small intestine. The Journal of experimental medicine 174 14744993
2001 CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease. Gastroenterology 171 11487533
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2008 Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clinical cancer research : an official journal of the American Association for Cancer Research 118 18245522
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2011 A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity. Immunity 100 21511186
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2004 Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clinical cancer research : an official journal of the American Association for Cancer Research 79 15623660
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2020 Intratumoral delivery of CCL25 enhances immunotherapy against triple-negative breast cancer by recruiting CCR9+ T cells. Science advances 74 32064335
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2011 CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis. Gastroenterology 74 22079594
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2005 V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement. Journal of immunology (Baltimore, Md. : 1950) 61 16210593
2019 Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis. Brain : a journal of neurology 60 30770703
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2017 Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis. Arthritis & rheumatology (Hoboken, N.J.) 52 28622456
2010 Retinoic acid-induced CCR9 expression requires transient TCR stimulation and cooperativity between NFATc2 and the retinoic acid receptor/retinoid X receptor complex. Journal of immunology (Baltimore, Md. : 1950) 52 21148038
2008 Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 51 18453568
2022 A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs. Angewandte Chemie (International ed. in English) 50 34936714
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2011 CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion. World journal of surgical oncology 47 21539750
2010 CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. International journal of cancer 47 20127861
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2010 Monocytes/macrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation. Arthritis research & therapy 46 20738854
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2020 CCR9 and CCL25: A review of their roles in tumor promotion. Journal of cellular physiology 44 32401349
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2007 CCR7, CCR8, CCR9 and CCR10 in the mouse hippocampal CA1 area and the dentate gyrus during and after pilocarpine-induced status epilepticus. Journal of neurochemistry 39 17181556
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2010 CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion. Journal of ovarian research 31 20565782
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2018 CD33+ CD14+ CD11b+ HLA-DR- monocytic myeloid-derived suppressor cells recruited and activated by CCR9/CCL25 are crucial for the pathogenic progression of endometriosis. American journal of reproductive immunology (New York, N.Y. : 1989) 30 30375700
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2010 Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells. Cellular & molecular immunology 27 20081876
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2021 CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts. European journal of immunology 21 33347617
2021 The Heteromeric Complex Formed by Dopamine Receptor D5 and CCR9 Leads the Gut Homing of CD4+ T Cells Upon Inflammation. Cellular and molecular gastroenterology and hepatology 21 33864900
2021 IL-17 and CCR9+α4β7- Th17 Cells Promote Salivary Gland Inflammation, Dysfunction, and Cell Death in Sjögren's Syndrome. Frontiers in immunology 21 34539657
2019 CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut. European journal of immunology 21 31755547