Affinage

CCR8

C-C chemokine receptor type 8 · UniProt P51685

Length
355 aa
Mass
40.8 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCR8 is a Gi-coupled seven-transmembrane chemokine receptor that directs the trafficking and function of Th2 cells, regulatory T cells, and dendritic cells in immune regulation and inflammation (PMID:9207005, PMID:9670926, PMID:11560999, PMID:30170811). It was identified as the specific receptor for the CC chemokine I-309/CCL1, conferring calcium flux and chemotaxis in heterologous cells through a pertussis toxin-sensitive Gi protein (PMID:9207005, PMID:9211859), and additional endogenous agonists CCL8 and CCL18 were subsequently established by binding, calcium flux, and chemotaxis in transfected and Ccr8-deficient cells (PMID:21217759, PMID:23999500). Viral chemokines define its pharmacology: HHV-8/KSHV vMIP-I acts as a selective agonist, whereas vMIP-II, vMCC-I, and the molluscum contagiosum-encoded MC148 are selective antagonists (PMID:10419462, PMID:10377196, PMID:10620615). Ligand binding requires post-translational sulfation of N-terminal tyrosines Y14/Y15 (PMID:14736884), and cryo-EM of CCR8-Gi complexes resolved a conserved Y1.39Y3.32E7.39 orthosteric motif and the nonpeptide binding pocket anchored by Glu286 (PMID:17652183, PMID:38306437). Downstream, CCR8 activates the RAS/ERK pathway to deliver anti-apoptotic signaling in thymocytes (PMID:12525579, PMID:12645948), couples to NF-κB/JNK in macrophages (PMID:24714157), and engages β-arrestin-dependent internalization and biased agonism (PMID:17023422, PMID:33872569). In regulatory T cells, CCL1-CCR8-STAT3 signaling upregulates FOXP3, CD39, IL-10, and granzyme B to enhance suppression (PMID:28533380), and CCR8 is selectively induced on highly suppressive tumor-infiltrating Tregs via TCR/NF-κB and TNF-α/TNFR2/NF-κB signaling and by H3K18-lactylation of its promoter (PMID:33589525, PMID:37770937, PMID:37935468); ADCC-competent anti-CCR8 antibodies deplete these Tregs and restore antitumor immunity (PMID:33589525). CCR8 also serves as an HIV-1 coreceptor (PMID:9417093, PMID:9480837, PMID:10888633) and is required for CCR8+ Treg-mediated maternal-fetal tolerance (PMID:40249828).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Established CCR8's founding identity by showing the orphan receptor CY6/TER1/CKR-L1 is the specific, Gi-coupled receptor for the CC chemokine I-309/CCL1.

    Evidence Heterologous transfection of pre-B cells with calcium flux, radioligand binding, chemotaxis, and pertussis toxin inhibition

    PMID:9207005 PMID:9211859

    Open questions at the time
    • Did not define downstream effector pathways beyond Gi coupling
    • Physiological cell types expressing CCR8 only partially mapped (monocytes, thymus)
  2. 1998 High

    Linked CCR8 to a defined immune compartment by demonstrating selective expression on Th2-polarized T cells and activation-induced, IL-4-independent upregulation.

    Evidence RT-PCR/Northern blot, mouse CCR8 cloning, chemotaxis, flow cytometry with anti-IL-4 neutralization in polarized primary T cells

    PMID:9670926 PMID:9820476

    Open questions at the time
    • Did not establish in vivo function of Th2-restricted CCR8
    • Ligand repertoire beyond I-309 still ambiguous at this stage
  3. 1998 High

    Identified CCR8 as an HIV-1 coreceptor whose endogenous ligand blocks viral entry, connecting the receptor to viral pathogenesis.

    Evidence Cell-cell fusion and infection assays across T-tropic, dual-tropic, and macrophage-tropic strains with I-309 inhibition; later extended to primary thymocytes

    PMID:10888633 PMID:9417093 PMID:9480837

    Open questions at the time
    • Relative contribution of CCR8 versus dominant coreceptors in vivo unresolved
    • Structural basis of gp120-CCR8 engagement not defined
  4. 1999 High

    Defined CCR8's viral chemokine pharmacology, distinguishing agonist from antagonist ligands and establishing its ligand-binding fingerprint.

    Evidence Large-panel (65-chemokine) competition binding, calcium mobilization, chemotaxis, and antagonism assays in transfected cells; MC148 added selective antagonist

    PMID:10377196 PMID:10419462 PMID:10620615

    Open questions at the time
    • Did not resolve structural determinants of agonist versus antagonist behavior
    • Physiological relevance of viral ligand engagement in infected hosts not addressed
  5. 2003 Medium

    Established the anti-apoptotic signaling output of CCR8 by mapping CCL1/vMIP-I activation to the RAS/MEK/ERK cascade in thymocytes.

    Evidence ERK phosphorylation, MEK inhibitor (PD98059), dominant-negative M-RAS, MC148 antagonism, and apoptosis assays in thymic lymphoma and CHO cells

    PMID:12525579 PMID:12645948

    Open questions at the time
    • Single-lab pathway dissection
    • In vivo relevance of thymocyte survival signaling not tested
  6. 2004 High

    Identified the post-translational requirement for ligand binding by showing N-terminal tyrosine sulfation (Y14/Y15) is essential for CCL1 recognition.

    Evidence Site-directed mutagenesis (Tyr→Phe, glycosylation-site mutants) with CCL1-Fc binding and calcium flux readouts on mouse CCR8

    PMID:14736884

    Open questions at the time
    • Sulfotransferase responsible not identified
    • Generalization to human CCR8 ligands beyond CCL1 not tested in this study
  7. 2007 High

    Defined the nonpeptide ligand-binding pocket and established CCR8's role in Treg suppressive programming via CCL1-STAT3-FOXP3 signaling.

    Evidence Extensive mutagenesis (25 residues) identifying Glu286 anchor; separately STAT3 inhibitor studies, CCR8-/- mice, and CCL1-Ig administration in EAE

    PMID:17652183 PMID:28533380

    Open questions at the time
    • Mechanism linking Glu286 to receptor trafficking versus binding only partially separated
    • STAT3-FOXP3 axis tested largely in autoimmune, not tumor, context at this stage
  8. 2006 Medium

    Resolved the trafficking and biased-signaling logic of CCR8 by showing β-arrestin-dependent internalization separable from Gi signaling and allotropic ligand binding sites.

    Evidence β-arrestin knockdown, internalization assays, Glu286/Asp97 mutagenesis, partial agonist Ser-CCL1, and differential CCL7 antagonism; later extended to biased agonism profiling

    PMID:17023422 PMID:33872569

    Open questions at the time
    • Functional consequences of biased agonism in vivo undefined
    • Single-lab arrestin dependence without reciprocal genetic confirmation
  9. 2011 High

    Expanded the endogenous ligand set and tissue function by establishing CCL8 (and later CCL18) as selective CCR8 agonists driving Th2 recruitment in allergic inflammation.

    Evidence Calcium flux/chemotaxis in transfected cells, Ccr8-/- and Ccl8-/- mice, adoptive transfer in atopic dermatitis and cross-desensitization with Ccr8-/- Th2 cells

    PMID:21217759 PMID:23999500

    Open questions at the time
    • Hierarchy among CCL1/CCL8/CCL18 in distinct tissues not fully resolved
    • Species differences in CCL8/CCR8 usage incompletely mapped
  10. 2018 High

    Defined CCR8's role in dendritic cell positioning by showing CCL8-CCR8-Src signaling is required for CD301b+ DC migration into lymph node parenchyma and downstream Th2 differentiation.

    Evidence CCR8-/- mice, intravital imaging, Src-kinase inhibition, and in vitro migration with CCL8/CCL21 synergy

    PMID:30170811

    Open questions at the time
    • Mechanism of CCL8/CCL21 synergy at the receptor level not defined
    • Whether this DC axis operates outside allergen contexts unknown
  11. 2021 High

    Established CCR8 as a therapeutic target on tumor-infiltrating Tregs, showing TCR/NF-κB-driven selective expression and ADCC-dependent (not blockade-dependent) Treg depletion as the antitumor mechanism.

    Evidence scRNA-seq, NF-κB inhibitor, ADCC-competent versus ADCC-deficient nanobody-Fc, NK depletion, syngeneic tumor models; epigenetic and TNFR2 routes added later

    PMID:33589525 PMID:37770937 PMID:37935468

    Open questions at the time
    • Whether CCR8 has an intrinsic functional role in ti-Treg suppression versus being a depletion marker not fully separated
    • Lactylation and TNFR2 mechanisms shown in single labs
  12. 2024 High

    Provided the structural framework for CCR8 ligand recognition and selectivity by resolving cryo-EM structures of CCR8-Gi complexes in ligand-free and agonist-bound states.

    Evidence Cryo-EM of CCR8-Gi with nonpeptide agonists LMD-009 and ZK 756326, plus functional mutagenesis of the Y1.39Y3.32E7.39 motif

    PMID:38306437

    Open questions at the time
    • No structure with endogenous chemokine ligand bound
    • Conformational basis of biased agonism not captured
  13. 2025 High

    Extended CCR8's regulatory T cell function to reproductive immunology by establishing CCR8+ decidual Tregs as required for maternal-fetal tolerance.

    Evidence Single-cell transcriptomics, TCR sequencing, CCR8+ Treg depletion and adoptive-transfer rescue in an abortion-prone mouse model, with decidual NK-derived CCL1 identified

    PMID:40249828

    Open questions at the time
    • Signaling output of CCR8 in decidual Tregs not dissected
    • Human causal evidence limited to enrichment/correlation

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether CCR8 signaling is intrinsically required for tumor-infiltrating Treg suppressive function, or whether CCR8 is principally a depletion-enabling surface marker, and how biased/allotropic ligand engagement translates into distinct in vivo outcomes.
  • No genetic separation of CCR8 signaling from CCR8 expression in ti-Tregs
  • Structural basis of biased agonism with endogenous ligands undefined
  • Tissue-specific ligand hierarchy (CCL1/CCL8/CCL18) not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0001618 virus receptor activity 2
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ARRB1ARRB2CCL1CCL18CCL8GNAI1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CCR8 (then named CY6/TER1/CKR-L1) was identified as the specific receptor for the human CC chemokine I-309 (CCL1). Transfection of the CY6 open reading frame into mouse pre-B cells conferred calcium flux and chemotaxis in response to I-309 (EC50 = 2 nM), while 20 other chemokines were inactive. Signaling was sensitive to pertussis toxin, indicating coupling to a Gi-type G protein. CCR8 is constitutively expressed in monocytes and thymus. Transfection of pre-B cell line, calcium flux assay, chemotaxis assay, pertussis toxin inhibition The Journal of experimental medicine High 9207005
1997 CCR8 (TER1/ChemR1/CKR-L1) stably expressed in murine pre-B 300-19 cells responds selectively to I-309 with intracellular Ca2+ mobilization and chemotaxis (Kd ~1.2 nM for 125I-I-309 binding), with no response to 20 other human chemokines tested. Stable transfection in 300-19 pre-B cells, 125I-I-309 radioligand binding, calcium mobilization, chemotaxis assay The Journal of biological chemistry High 9211859
1998 TARC (CCL17) and MIP-1β (CCL4) were identified as additional functional CCR8 ligands, inducing chemotaxis in CCR8-transfected Jurkat cells. Stable transfection of Jurkat cells, chemotaxis assay European journal of immunology Medium 9521068
1998 CCR8 is preferentially expressed in Th2-polarized T cells (human and mouse) but not Th1 cells. Mouse CCR8 is also expressed in thymus and NK1.1+CD4+ T cells. I-309 and its mouse homologue TCA-3 are potent chemoattractants for Th2-polarized cells acting through CCR8. RT-PCR, Northern blot, chemotaxis assay, mouse CCR8 cloning Journal of immunology High 9670926
1998 CCR8 expression on Th2 cells is transiently up-regulated following TCR and CD28 engagement (activation-induced), and this up-regulation occurs independently of IL-4. Functional chemotactic responsiveness to I-309 is correspondingly enhanced upon activation. Flow cytometry, chemotaxis assay, cytokine neutralization (anti-IL-4) Journal of immunology Medium 9820476
1998 CCR8 functions as a coreceptor for diverse HIV-1 strains (T-cell tropic, dual-tropic, and macrophage-tropic), and the CCR8 ligand I-309 potently inhibits HIV-1 envelope-mediated cell-cell fusion and virus infection. Cell-cell fusion assay, virus infection assay, flow cytometry, Ca2+ flux assay The Journal of biological chemistry High 10888633 9417093 9480837
1999 HHV-8-encoded vMIP-I is a selective CCR8 agonist: it binds CCR8 with high affinity (Kd <15 nM), induces Ca2+ signals in human T cells selectively through CCR8, and acts as agonist. By contrast, viral chemokines vMIP-II and vMCC-I act as potent CCR8 antagonists (binding without inducing signaling, blocking I-309 effects). A panel of 65 chemokines was used to establish CCR8 ligand selectivity. Calcium mobilization assay, competition binding assay with 65 chemokines, antagonism assay The Journal of biological chemistry High 10419462
1999 vMIP-I (KSHV-encoded) is a specific agonist for CCR8: CCR8-transfected Y3 cells showed calcium flux and vigorous chemotaxis in response to vMIP-I, with high-affinity competitive binding, and no interaction with CCR5 or 11 other receptors tested. Calcium flux assay, in vitro chemotaxis, competition binding assay in CCR8-transfected cells The Journal of experimental medicine High 10377196
2000 MC148, encoded by the poxvirus molluscum contagiosum, is a highly selective CCR8 antagonist: it binds only CCR8 (among 16 classified human chemokine receptors), blocks I-309-induced Ca2+ signaling and chemotaxis through CCR8 without acting as agonist, and does not affect signaling of any other chemokine receptor. Competition binding with radiolabeled chemokines, calcium mobilization assay, chemotaxis assay across 16 chemokine receptors The Journal of experimental medicine High 10620615
2001 CCR8 is expressed on human umbilical vein endothelial cells (HUVECs) and mediates endothelial cell chemotaxis induced by I-309 and vMIP-I; this chemotaxis is blocked by anti-CCR8 antibody and pertussis toxin, demonstrating Gi-coupled receptor-mediated signaling in endothelial cells. Chemotaxis assay, antibody blocking, pertussis toxin inhibition, RNA blot, immunohistochemistry Blood Medium 11133740
2001 CCR8 is specifically expressed on circulating CD4+CD25+ regulatory T cells (Tregs) and mediates their chemotactic response to CCL1 and CCL22; mature dendritic cells preferentially attract Tregs by secreting CCR4 ligands CCL17 and CCL22, positioning Tregs at sites of antigen presentation. Flow cytometry, chemotaxis assay, FACS-based sorting, alloproliferative response assay The Journal of experimental medicine Medium 11560999
2003 CCR8 mediates human vascular smooth muscle cell (VSMC) chemotaxis induced by CCL1 and vMIP-I via a G-protein-dependent mechanism (blocked by anti-CCR8 mAb and pertussis toxin). CCL1 also induces CCR8-dependent pro-MMP-2 mRNA and protein secretion from VSMCs, and the poxvirus CCR8 antagonist MC148 inhibited CCL1-induced MMP-2 induction, confirming CCR8 dependence. Chemotaxis assay, antibody blocking, pertussis toxin inhibition, RT-PCR, Western blot for MMP-2, MC148 antagonism Blood Medium 14576057
2003 CCR8 activation by CCL1 or vMIP-I mediates rescue from dexamethasone-induced apoptosis in murine thymic lymphoma cells and primary thymocytes via ERK-dependent signaling; the selective CCR8 antagonist MC148/vMCC-I blocks this anti-apoptotic effect, formally establishing CCR8 as the receptor responsible. Apoptosis assay, ERK phosphorylation assay, MC148 antagonism, pertussis toxin inhibition Journal of leukocyte biology Medium 12525579
2003 CCR8 activation by CCL1 or vMIP-I activates the RAS/MAPK pathway (ERK1/2 phosphorylation) in BW5147 thymic lymphoma cells and CCR8-transfected CHO cells, mediating anti-apoptotic activity. PD98059 (MEK inhibitor) and dominant-negative M-RAS blocked CCL1 anti-apoptotic activity. ERK phosphorylation assay, CHO transfection, MEK inhibitor (PD98059), dominant-negative M-RAS expression, apoptosis assay European journal of immunology Medium 12645948
2004 Post-translational sulfation of tyrosines Y14 and Y15 in the N-terminal domain of mouse CCR8 is critical for its ligand-binding activity; Y14Y15→F14F15 double mutant showed markedly reduced sulfation and was essentially inactive for CCL1 binding and calcium flux. N-linked glycosylation at N8 and O-linked glycosylation at T10/T12 had minor effects on ligand binding. Site-directed mutagenesis (Tyr→Phe, Asn→Gln, Thr→Ala substitutions), flow cytometry with CCL1-Fc fusion, calcium flux assay The Journal of biological chemistry High 14736884
2005 LEC (CCL16) induces chemotaxis and cell adhesion by binding to and activating both CCR1 and CCR8 transfected HEK-293 cells, though at higher molar concentrations than RANTES or I-309 respectively. Chemotaxis assay, competition binding assay in CCR1- and CCR8-transfected HEK-293 cells, neutralizing antibody validation Blood Medium 10910894
2007 A nonpeptide CCR8 agonist LMD-009 selectively activates CCR8 among 20 human chemokine receptors, mediating chemotaxis, inositol phosphate accumulation, and calcium release (EC50 11–87 nM). Systematic mutagenesis of 25 amino acids identified Glu286 (VII:06) as a critical anchor-point (loss of potency ~1000-fold upon Ala substitution) and Phe254 (VI:16) as a gain-of-function site for LMD-009, defining the nonpeptide ligand-binding pocket. Mutagenesis of 29 positions targeting 25 residues, calcium release assay, chemotaxis assay, IP accumulation assay, 125I-CCL1 competition binding Molecular pharmacology High 17652183
2006 CCR8 receptor internalization is dependent on β-arrestins 1 and 2 but independent of Gαi signaling. The N-terminus of CCL1 plays a role in ligand binding to an intrahelical site; Glu-286 (TM helix 7) is crucial for receptor trafficking to the cell surface. CCL7 selectively antagonizes CCR8 responses to vMIP-I and partial agonist Ser-CCL1 but not to CCL1 itself, suggesting allotropic binding of CCR8 ligands at distinct sites. Calcium flux assay, chemotaxis assay, receptor internalization assay, β-arrestin KD, pertussis toxin treatment, mutagenesis (Glu-286, Asp-97), partial agonist (Ser-CCL1) synthesis The Journal of biological chemistry Medium 17023422
2007 CCL1 signaling through CCR8 on Tregs induces STAT3-dependent up-regulation of FOXP3, CD39, IL-10, and granzyme B, enhancing suppressive activity. Among four human CCR8 ligands, CCL1 is unique in potentiating Treg function. A self-feeding mechanism was identified whereby CCL1 produced by Tregs at autoimmune sites up-regulates CCR8 expression on these cells. CCR8-/- mice showed impaired Treg function in EAE adoptive transfer studies. Flow cytometry, STAT3 inhibitor studies, adoptive transfer in EAE model, CCR8-/- mice, CCL1-Ig administration Proceedings of the National Academy of Sciences of the United States of America High 28533380
2007 CCR8 is required for CCL1-mediated macrophage aggregation and peritoneal adhesion: CCR8 is up-regulated on peritoneal macrophages by inflammatory stimuli and CCL1 itself (autocrine loop). CCL1 also up-regulates plasminogen activator inhibitor-1 mRNA in macrophages and mesothelial cells. CCR8-/- mice showed significantly reduced postoperative peritoneal adhesions. In vitro cell aggregation assay, RT-PCR, CCR8-/- mice, anti-CCL1 neutralizing antibody treatment, in vivo adhesion model Journal of immunology Medium 17404314
2007 Mast cell-derived CCL1 acts through CCR8 on CD4+ T cells to orchestrate mucosal lung inflammatory responses. CCR8 deficiency results in reduced airway hyperresponsiveness, lung inflammation, and mucus hypersecretion comparable to mast cell-deficient mice; adenoviral CCL1 delivery to mast cell-deficient mouse lungs restored these parameters, establishing a mast cell-CCL1-CCR8-T cell axis. CCR8-/- mice, mast cell-deficient mice, adenoviral gene delivery, CCL1 neutralization, airway hyperresponsiveness measurement, BALF cytokine analysis Journal of immunology High 17641040
2011 Mouse CCL8 is a selective agonist for CCR8 but not CCR2 (distinguishing it from other MCP chemokines). CCR8 expression defines a population of highly differentiated inflammatory Th2 cells enriched for IL-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type mice in a chronic atopic dermatitis model. Adoptive transfer experiments established CCR8 as a key regulator of Th2 cell recruitment into allergen-inflamed skin. Calcium flux, chemotaxis assay in CCR8-transfected cells, Ccr8-/- and Ccl8-/- mouse models, adoptive transfer, flow cytometry Nature immunology High 21217759
2013 Human CCR8 is a receptor for CCL18: CCL18 induced chemotaxis and calcium flux in CCR8-transfected cells, bound with high affinity, induced CCR8 internalization, and competed for CCL1 binding. CCL1 and CCL18 induced heterologous cross-desensitization of CCR8-transfected cells and human Th2 cells. Wild-type but not Ccr8-/- mouse Th2 cells migrated in response to CCL18. Chemotaxis assay, calcium flux, radiolabeled competition binding, receptor internalization, cross-desensitization assay, Ccr8-/- mice The Journal of experimental medicine High 23999500
2012 C-terminal clipping of CCL1/I-309 by carboxypeptidase M (CPM) augments CCR8-mediated intracellular calcium release and anti-apoptotic activity while reducing direct CCL1 binding to CCR8, demonstrating that proteolytic processing modulates the CCL1-CCR8 signaling axis. In vitro enzymatic cleavage by CPM, mass spectrometry, calcium flux assay, CCR8 binding assay, apoptosis assay, carboxypeptidase inhibitor control PloS one Medium 22479563
2018 CCR8 on CD301b+ dendritic cells (DCs) is required for their migration from the subcapsular sinus into lymph node parenchyma after allergen exposure. CCR8 ligand CCL8 is produced by CD169+SIGN-R1+ macrophages in interfollicular regions after allergen exposure and synergizes with CCL21 in a Src-kinase-dependent manner to promote DC migration. In CCR8-deficient mice, CD301b+ DCs accumulated in the subcapsular sinus and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. CCR8-/- mice, intravital microscopy/flow cytometry, Src-kinase inhibitor, in vitro migration assay, Th2 differentiation assay Immunity High 30170811
2019 Activated ILC2s produce CCL1 (the CCR8 ligand) and are a major source of CCL1 in vivo; CCL1 signaling through CCR8 on ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections (rather than primarily mediating ILC2 migration). In vitro CCL1 production assays, in vivo helminth infection model, CCR8-/- mice, proliferation assay The Journal of experimental medicine Medium 31537642
2014 CCR8 is required for LPS-triggered cytokine production (TNF-α, IL-6, IL-10) in peritoneal macrophages but not bone marrow-derived macrophages. CCR8-/- peritoneal macrophages showed attenuated c-Jun N-terminal kinase activity and NF-κB signaling after LPS treatment, revealing cross-talk between CCR8 and TLR-4 signaling pathways. The CCR8 antagonist R243 recapitulated CCR8-/- phenotypes. CCR8-/- mice, ELISA, CCR8 antagonist R243, JNK assay, NF-κB signaling assay, in vivo peritoneal adhesion and colitis models PloS one Medium 24714157
2021 CCR8 expression on tumor-infiltrating Tregs results from TCR-mediated triggering in an NF-κB-dependent fashion. CCR8 protein is selectively prominent on highly activated, strongly suppressive tumor-infiltrating Treg subpopulations in both mouse and human tumors, with minimal CCR8-positivity on peripheral Tregs. Depletion of CCR8+ ti-Tregs by ADCC-prone anti-CCR8 nanobody-Fc in a NK-cell-dependent manner elicited antitumor immunity and reduced tumor growth; ADCC-deficient blocking antibody had no effect, indicating that Treg depletion (not CCR8 blockade) is the mechanism of antitumor activity. Single-cell RNA-seq, flow cytometry, NF-κB inhibitor, nanobody-Fc constructs with/without ADCC, NK cell depletion, syngeneic mouse tumor models (LLC-OVA, MC38) Journal for immunotherapy of cancer High 33589525
2024 Three cryo-EM structures of human CCR8 complexed with Gi trimers were solved in the ligand-free state and activated by nonpeptide agonists LMD-009 and ZK 756326. A conserved Y1.39Y3.32E7.39 motif in the orthosteric binding pocket plays a crucial role in chemokine and nonpeptide ligand recognition. Lack of conservation in Y1143.33 and Y1724.64 among CC chemokine receptors contributes to nonpeptide ligand selectivity for CCR8. Cryo-electron microscopy, structural analysis, mutagenesis (functional validation of key residues) Science advances High 38306437
2021 CCR8-mediated signaling is biased: human CCL1 induces cell migration via Gβγ-dependent signaling, whereas other CCR8 agonists (vCCL1, ZK756326, AZ6) induce migration independently of Gβγ. All agonists were full agonists for calcium mobilization; CCR8 agonists predominantly induce Gαi-dependent cellular impedance signaling. Small molecule agonists display higher efficacy in β-arrestin 1 recruitment, occurring independently of Gαi, classifying them as biased agonists. hCCL1-AF647 binding assay, calcium mobilization, cellular impedance, chemotaxis, β-arrestin 1/2 recruitment assay, Gβγ inhibitor (gallein), Gαi inhibitor (pertussis toxin) Biochemical pharmacology Medium 33872569
2022 Intracellular lactate directly elevates CCR8 expression in T cells and macrophages through histone H3K18 lactylation of the CCR8 gene promoter, as demonstrated by chromatin immunoprecipitation. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, RT-qPCR, Western blot, flow cytometry Journal of experimental & clinical cancer research Medium 37770937
2022 CCL8 from donor kidney resident macrophages promotes recipient monocyte graft infiltration via CCR8; CCR8+ T cells (CD4, CD8, γδ) infiltrate the allograft following CCL8 induction. Blocking CCL8-CCR8 or depleting donor kidney macrophages significantly inhibited early allograft immune cell infiltration and improved allograft function. Allogeneic kidney transplant mouse model, flow cytometry, CCL8-CCR8 blocking antibody, macrophage depletion Journal of the American Society of Nephrology Medium 35973731
2019 Disruption of the CCL1-CCR8 axis (via CCL1/Apoe double-KO mice or CCR8 blocking antibodies in LDLR-/- mice) promoted atherosclerosis, reduced plasma IL-10, increased Th1/Th2 ratio, and decreased regulatory T cell content in aorta and spleen. In vitro flow chamber assays and in vivo intravital microscopy demonstrated CCL1 mediates leukocyte recruitment to atherosclerotic vessels. Double-KO mice (Ccl1-/-/Apoe-/-), CCR8 blocking antibody in LDLR-/- mice, intravital microscopy, in vitro flow chamber, flow cytometry, ELISA Journal of molecular and cellular cardiology Medium 31121182
2024 TNF-α in the colorectal cancer microenvironment upregulates CCR8 expression in Tregs via the TNFR2/NF-κB signaling pathway and the FOXP3 transcription factor. Flow cytometry, Western blot, NF-κB pathway inhibition, TNFR2 knockout/blockade, luciferase reporter Journal of molecular cell biology Medium 37935468
2001 CCR8 functions as an HIV-1 coreceptor on primary human thymocytes: 125I-I-309 bound specifically to thymocyte surfaces, I-309 inhibited HIV-1 fusion with thymocytes in a dose-dependent manner, and I-309 partially inhibited productive infection by X4, R5, and X4R5 HIV-1 strains. 125I-I-309 binding assay on primary thymocytes, cell-cell fusion inhibition assay, productive HIV-1 infection assay Journal of virology Medium 10888633
2018 CCL18 promotes uptake of glycosylated extracellular vesicles (EVs) by glioblastoma cells via a triple interaction involving CCR8 on recipient cells, glycans on EVs, and CCL18 as a bridging molecule. EV-induced proliferation and temozolomide resistance are neutralized by the CCR8 small molecule inhibitor R243. RNAi screening, in vitro and in vivo glioblastoma models, CCR8 inhibitor R243, flow cytometry Journal of extracellular vesicles Medium 29696074
2022 CCL18 from microglia/macrophages promotes glioma cell growth and invasion via CCR8 as a functional receptor, with ACP5 (acid phosphatase 5) identified as an important downstream signaling component. This was validated in a humanized ex vivo slice model using iPSC-derived human microglia and in an in vivo GBM model. Humanized brain slice model (iPSC-derived human microglia), CCR8 receptor identification, ACP5 downstream signaling, in vivo GBM mouse model Cell reports Medium 35417708
2021 CCL1 from tumor-associated macrophages promotes esophageal squamous cell carcinoma cell motility via CCR8 on cancer cells through the Akt/PRAS40/mTOR pathway; PI3K/Akt inhibitors, CCR8 knockdown, and anti-CCR8 neutralizing antibody suppressed CCL1-induced effects. Neutralizing antibody, siRNA knockdown of CCR8, PI3K/Akt inhibitors, motility assay, Western blot The American journal of pathology Medium 33460563
2025 CCR8+ Tregs are specifically enriched in human decidua during first-trimester pregnancy and are required for maternal-fetal tolerance. Depletion of CCR8+ dTreg cells increased fetal loss susceptibility in an abortion-prone mouse model, and adoptive transfer of CCR8+ Tregs rescued fetal loss. CCL1 produced by decidual CD49a+ natural killer cells is the primary CCR8 ligand in this context. Single-cell transcriptomics, TCR sequencing, CCR8+ Treg depletion, adoptive transfer, flow cytometry, CCL1 ELISA Science immunology High 40249828

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. The Journal of experimental medicine 713 11560999
1998 Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. Journal of immunology (Baltimore, Md. : 1950) 346 9820476
2001 The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. The Journal of clinical investigation 333 11390417
1998 The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells. Journal of immunology (Baltimore, Md. : 1950) 329 9670926
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 308 33076281
2011 Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nature immunology 261 21217759
2017 CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proceedings of the National Academy of Sciences of the United States of America 196 28533380
1997 Identification of CCR8: a human monocyte and thymus receptor for the CC chemokine I-309. The Journal of experimental medicine 179 9207005
2005 CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation. Journal of immunology (Baltimore, Md. : 1950) 174 15814739
2021 Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy. Journal for immunotherapy of cancer 168 33589525
2013 Identification of human CCR8 as a CCL18 receptor. The Journal of experimental medicine 158 23999500
2022 CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory. Proceedings of the National Academy of Sciences of the United States of America 156 35140181
1999 HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and antagonist profiles of viral chemokines. The Journal of biological chemistry 148 10419462
1997 Identification of CCR8, the receptor for the human CC chemokine I-309. The Journal of biological chemistry 147 9211859
1998 The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains. The Journal of biological chemistry 143 9417093
2023 Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation. Journal of experimental & clinical cancer research : CR 136 37770937
1999 The Kaposi's sarcoma-related herpesvirus (KSHV)-encoded chemokine vMIP-I is a specific agonist for the CC chemokine receptor (CCR)8. The Journal of experimental medicine 117 10377196
2006 CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 115 17082609
2000 A highly selective CC chemokine receptor (CCR)8 antagonist encoded by the poxvirus molluscum contagiosum. The Journal of experimental medicine 108 10620615
2018 Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer. Cancer research 107 30026324
2008 Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation. The Journal of allergy and clinical immunology 105 19062085
2007 TER1, the RNA subunit of fission yeast telomerase. Nature structural & molecular biology 101 18157152
2021 Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models. Cancer research 100 33757978
2018 The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response. Immunity 99 30170811
2007 Identification and characterization of the Schizosaccharomyces pombe TER1 telomerase RNA. Nature structural & molecular biology 96 18157149
1998 Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor. European journal of immunology 91 9521068
2003 CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease. Journal of immunology (Baltimore, Md. : 1950) 83 12496446
2018 Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8. Journal of extracellular vesicles 80 29696074
2022 Tumor-derived exosomes drive pre-metastatic niche formation in lung via modulating CCL1+ fibroblast and CCR8+ Treg cell interactions. Cancer immunology, immunotherapy : CII 78 35428909
2003 Absence of CCR8 does not impair the response to ovalbumin-induced allergic airway disease. Journal of immunology (Baltimore, Md. : 1950) 77 12574386
2018 CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin. Journal of immunology (Baltimore, Md. : 1950) 76 29427415
1998 Identification of the chemokine receptor TER1/CCR8 expressed in brain-derived cells and T cells as a new coreceptor for HIV-1 infection. Biochemical and biophysical research communications 75 9480837
2021 CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function. Immunology 74 33838058
2001 The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium. Blood 72 11133740
1998 Identification of CCR8 as the specific receptor for the human beta-chemokine I-309: cloning and molecular characterization of murine CCR8 as the receptor for TCA-3. Journal of immunology (Baltimore, Md. : 1950) 65 9469461
2007 Recruitment and activation of macrophages by pathogenic CD4 T cells in type 1 diabetes: evidence for involvement of CCR8 and CCL1. Journal of immunology (Baltimore, Md. : 1950) 64 17947648
2003 Chemokine receptor-8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion. Blood 61 14576057
2019 A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation. The Journal of experimental medicine 60 31537642
2005 CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice. Journal of immunology (Baltimore, Md. : 1950) 58 15699124
2013 Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 56 23363815
2007 Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions. Journal of immunology (Baltimore, Md. : 1950) 56 17404314
2007 Coordinated involvement of mast cells and T cells in allergic mucosal inflammation: critical role of the CC chemokine ligand 1:CCR8 axis. Journal of immunology (Baltimore, Md. : 1950) 56 17641040
1996 Molecular cloning of TER1, a chemokine receptor-like gene expressed by lymphoid tissues. Journal of immunology (Baltimore, Md. : 1950) 53 8816377
2003 CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I. European journal of immunology 48 12645948
2013 Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis. Journal of hepatology 47 23811304
2007 Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8. Molecular pharmacology 47 17652183
2005 Sap1p binds to Ter1 at the ribosomal DNA of Schizosaccharomyces pombe and causes polar replication fork arrest. The Journal of biological chemistry 47 16195226
2018 CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells. Molecular medicine reports 46 30592282
2002 Increased responsiveness of murine eosinophils to MIP-1beta (CCL4) and TCA-3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8. Journal of leukocyte biology 46 12050188
2020 CCR8 blockade primes anti-tumor immunity through intratumoral regulatory T cells destabilization in muscle-invasive bladder cancer. Cancer immunology, immunotherapy : CII 45 32367308
2000 CCR8 on human thymocytes functions as a human immunodeficiency virus type 1 coreceptor. Journal of virology 44 10888633
2022 The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer. Scientific reports 42 35354899
2000 LEC induces chemotaxis and adhesion by interacting with CCR1 and CCR8. Blood 41 10910894
2019 Disruption of the CCL1-CCR8 axis inhibits vascular Treg recruitment and function and promotes atherosclerosis in mice. Journal of molecular and cellular cardiology 40 31121182
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
2022 Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody. Oncoimmunology 38 36352891
2003 The chemokine receptor CCR8 mediates rescue from dexamethasone-induced apoptosis via an ERK-dependent pathway. Journal of leukocyte biology 38 12525579
2017 Spinal CCL1/CCR8 signaling interplay as a potential therapeutic target - Evidence from a mouse diabetic neuropathy model. International immunopharmacology 37 28961489
2012 Schizosaccharomyces pombe Ccq1 and TER1 bind the 14-3-3-like domain of Est1, which promotes and stabilizes telomerase-telomere association. Genes & development 36 22215813
2004 Analysis of post-translational CCR8 modifications and their influence on receptor activity. The Journal of biological chemistry 36 14736884
2014 Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages. PloS one 35 24714157
2021 Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway. Frontiers in immunology 34 34025655
2010 Expression of CCR8 is increased in asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 20455898
2010 Coreceptor usage by HIV-1 and HIV-2 primary isolates: the relevance of CCR8 chemokine receptor as an alternative coreceptor. Virology 34 20947116
2006 Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8 (CCR8). Journal of medicinal chemistry 33 16640325
2024 Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+T regulatory cells. Journal of molecular cell biology 32 37935468
2022 Microglia/macrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model. Cell reports 31 35417708
2006 Structure/function relationships of CCR8 agonists and antagonists. Amino-terminal extension of CCL1 by a single amino acid generates a partial agonist. The Journal of biological chemistry 31 17023422
2022 Chemokine Receptor-Targeted Therapies: Special Case for CCR8. Cancers 29 35158783
2005 Identification and characterization of a potent, selective nonpeptide agonist of the CC chemokine receptor CCR8. Molecular pharmacology 28 16221874
2025 CCR8: a promising therapeutic target against tumor-infiltrating regulatory T cells. Trends in immunology 27 39890548
2024 Targeting tumor-infiltrating CCR8+ regulatory T cells induces antitumor immunity through functional restoration of CD4+ Tconvs and CD8+ T cells in colorectal cancer. Journal of translational medicine 26 39080766
2023 S-531011, a Novel Anti-Human CCR8 Antibody, Induces Potent Antitumor Responses through Depletion of Tumor-Infiltrating CCR8-Expressing Regulatory T Cells. Molecular cancer therapeutics 25 37420296
2025 CCR8+ decidual regulatory T cells maintain maternal-fetal immune tolerance during early pregnancy. Science immunology 22 40249828
2025 Selective Depletion of CCR8+Treg Cells Enhances the Antitumor Immunity of Cytotoxic T Cells in Lung Cancer by Dendritic Cells. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 21 40056978
2022 Blocking CCL8-CCR8-Mediated Early Allograft Inflammation Improves Kidney Transplant Function. Journal of the American Society of Nephrology : JASN 21 35973731
2003 Genomic organization and evolution of the CX3CR1/CCR8 chemokine receptor locus. The Journal of biological chemistry 21 12551893
2023 Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer. Journal of medicinal chemistry 20 36988587
2021 Chemokine (C-C Motif) Ligand 1 Derived from Tumor-Associated Macrophages Contributes to Esophageal Squamous Cell Carcinoma Progression via CCR8-Mediated Akt/Proline-Rich Akt Substrate of 40 kDa/Mammalian Target of Rapamycin Pathway. The American journal of pathology 20 33460563
2012 C-terminal clipping of chemokine CCL1/I-309 enhances CCR8-mediated intracellular calcium release and anti-apoptotic activity. PloS one 20 22479563
2011 Orally bioavailable allosteric CCR8 antagonists inhibit dendritic cell, T cell and eosinophil migration. Biochemical pharmacology 20 22209712
2007 Combination of 17beta-estradiol with the environmental pollutant TCDD is involved in pathogenesis of endometriosis via up-regulating the chemokine I-309-CCR8. Fertility and sterility 20 17693327
2004 Genetic dissection of the Kluyveromyces lactis telomere and evidence for telomere capping defects in TER1 mutants with long telomeres. Eukaryotic cell 20 15075267
2007 Expression of chemokine receptors CCR7 and CCR8 in the CNS during ChREAE. Scandinavian journal of immunology 19 17850582
2023 Immunotherapy Targeting CCR8+ Regulatory T Cells Induces Antitumor Effects via Dramatic Changes to the Intratumor CD8+ T Cell Profile. Journal of immunology (Baltimore, Md. : 1950) 18 37350632
2011 CCR8 signaling influences Toll-like receptor 4 responses in human macrophages in inflammatory diseases. Clinical and vaccine immunology : CVI 17 21976223
2024 Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody. Clinical and experimental medicine 16 38856863
2022 C8Mab-3: An Anti-Mouse CCR8 Monoclonal Antibody for Immunocytochemistry. Monoclonal antibodies in immunodiagnosis and immunotherapy 16 35377236
2022 Development of an Anti-Mouse CCR8 Monoclonal Antibody (C8Mab-1) for Flow Cytometry and Immunocytochemistry. Monoclonal antibodies in immunodiagnosis and immunotherapy 16 35483056
2019 Spinal CCL1/CCR8 regulates phosphorylation of GluA1-containing AMPA receptor in postoperative pain after tibial fracture and orthopedic surgery in mice. Neuroscience research 16 31121204
2019 CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis. Scientific reports 16 31270368
2014 CCR8 regulates contact hypersensitivity by restricting cutaneous dendritic cell migration to the draining lymph nodes. International immunology 16 25344933
2001 MC148 encoded by human molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8. Journal of leukocyte biology 16 11493620
2024 Unveiling the structural mechanisms of nonpeptide ligand recognition and activation in human chemokine receptor CCR8. Science advances 15 38306437
2023 CD4+CCR8+ Tregs in ovarian cancer: a potential effector Tregs for immune regulation. Journal of translational medicine 15 37950246
2022 TGF-β-induced CCR8 promoted macrophage transdifferentiation into myofibroblast-like cells. Experimental lung research 15 35377281
2012 Molecular requirements for inhibition of the chemokine receptor CCR8--probe-dependent allosteric interactions. British journal of pharmacology 15 22708643
2007 Remission of chronic fungal asthma in the absence of CCR8. The Journal of allergy and clinical immunology 15 17321573
2021 Biological characterization of ligands targeting the human CC chemokine receptor 8 (CCR8) reveals the biased signaling properties of small molecule agonists. Biochemical pharmacology 14 33872569
2015 In silico characterization of binding mode of CCR8 inhibitor: homology modeling, docking and membrane based MD simulation study. Journal of biomolecular structure & dynamics 14 25617117

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