Affinage

CD6

T-cell differentiation antigen CD6 · UniProt P30203

Length
668 aa
Mass
71.8 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD6 is a type I transmembrane glycoprotein of the scavenger receptor cysteine-rich (SRCR) superfamily that functions as a dual costimulatory and inhibitory signaling hub at the T cell immunological synapse, integrating adhesion, pathogen sensing, and TCR signal modulation. Its membrane-proximal SRCR domain 3 binds the ligands CD166/ALCAM (KD ~0.4–1.0 µM) and CD318, mediating T cell–APC adhesion and targeting CD6 to the central SMAC where it physically associates with the TCR/CD3 complex and CD5 (PMID:7760007, PMID:15294938, PMID:28760953, PMID:12473675). TCR engagement triggers tyrosine phosphorylation of cytoplasmic residues Y629 and Y662, which bivalently recruit a GADS/SLP-76 signalosome independently of LAT, while also engaging the negative regulator UBASH3A/STS-2, thereby enabling CD6 to both promote and attenuate T cell activation depending on context; CD6 deficiency in mice causes augmented initial TCR signaling but impaired T cell survival, reduced Th1/Th17 responses, and protection from EAE (PMID:28289074, PMID:24584089, PMID:33125054, PMID:27377588, PMID:28209777). T cell activation induces alternative splicing of exon 5 (regulated by SRSF1 and chromatin acetylation) to produce a CD6Δd3 isoform lacking the ALCAM-binding domain that cannot localize to the immunological synapse, providing a feedback mechanism to tune CD6-mediated costimulation (PMID:17371992, PMID:24890719).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1989 High

    Establishing CD6 as a T cell costimulatory molecule: prior to this, CD6 (T12) was an orphan 130 kDa T cell surface glycoprotein; cross-linking with anti-CD3 demonstrated that it delivers IL-2-dependent co-activating signals to CD4+ T cells, requiring macrophage cofactors.

    Evidence In vitro T cell proliferation and IL-2R expression assays with anti-CD6/anti-CD3 co-crosslinking

    PMID:2481822 PMID:2794503

    Open questions at the time
    • Costimulatory ligand unknown
    • Signaling pathway downstream of CD6 uncharacterized
    • Contribution of macrophages mechanistically undefined
  2. 1991 High

    Molecular cloning and biochemical characterization revealed that CD6 is an SRCR superfamily member with extracellular SRCR domains and a cytoplasmic domain subject to serine phosphorylation and PKC-regulated electrophoretic mobility shifts, establishing its signaling potential.

    Evidence cDNA cloning, COS cell transfection, pulse-chase biosynthetic labeling, reversible phosphatase treatment

    PMID:1919444 PMID:2016320 PMID:2384666

    Open questions at the time
    • Tyrosine phosphorylation not yet examined
    • Ligand not identified
    • Relationship to TCR signaling unknown
  3. 1995 High

    Identification of ALCAM/CD166 as the CD6 ligand and mapping the interaction to SRCR domain 3 resolved the long-standing question of what CD6 binds, establishing this as the first characterized SRCR–Ig-domain receptor–ligand pair.

    Evidence COS cell adhesion assays, Ig fusion protein binding, domain-deletion constructs, mAb blocking

    PMID:7543097 PMID:7760007 PMID:8663238

    Open questions at the time
    • Binding affinity not yet quantified
    • In vivo relevance of CD6-ALCAM interaction unproven
    • Additional ligands suspected but not identified
  4. 1997 High

    Identification of Y629 and Y662 as the TCR-induced phosphorylation sites in the CD6 cytoplasmic domain, and demonstration that calcium mobilization maps to a distinct membrane-proximal region, established that CD6 signaling involves separable functional modules.

    Evidence Site-directed mutagenesis of chimeric receptors, anti-phosphotyrosine IP, calcium flux measurement in T cell lines

    PMID:7678115 PMID:9013954 PMID:9394826

    Open questions at the time
    • Downstream adaptor proteins binding phosphotyrosines unknown
    • In vivo significance of individual tyrosines untested
    • Contribution of alternatively spliced cytoplasmic isoforms unclear
  5. 2004 High

    Quantitative kinetic measurement of CD6–ALCAM interaction (KD 0.4–1.0 µM, fast off-rate) and demonstration that CD6 physically associates with TCR/CD3 at the central SMAC placed CD6 as an integral component of the immunological synapse required for optimal T cell responses.

    Evidence Surface plasmon resonance, co-immunoprecipitation, FRET, confocal microscopy of antigen-specific conjugates, soluble protein inhibition of proliferation

    PMID:15048703 PMID:15294938

    Open questions at the time
    • Mechanism of CD6 recruitment to TCR complex unknown
    • Role of second ligand (3A11/CD318) at IS undefined
    • Structural basis of CD6-TCR association unclear
  6. 2006 High

    Discovery that phospho-Y662 recruits SLP-76 directly and that CD6 ligation activates ERK1/2, p38, JNK, and AP-1 pathways identified the core costimulatory signaling cascade downstream of CD6.

    Evidence Phosphopeptide–SLP-76 SPR binding, Y662F mutagenesis abolishing costimulation, phospho-MAPK Western blots, reporter gene assays with Src kinase inhibitors

    PMID:16818773 PMID:16914752

    Open questions at the time
    • Whether SLP-76 recruitment to CD6 is LAT-dependent or independent not resolved
    • Identity of adaptor binding Y629 unknown
    • MAPK activation mechanism via CD6 vs. TCR not dissected
  7. 2007 High

    Discovery of the CD6Δd3 splice isoform (lacking exon 5/SRCR domain 3) that cannot localize to the immunological synapse and is upregulated upon T cell activation established a built-in feedback mechanism to modulate CD6-mediated costimulation.

    Evidence RT-PCR, confocal imaging of IS localization with domain-deleted construct, single-cell splice variant analysis

    PMID:17371992

    Open questions at the time
    • Splicing regulation mechanism unknown
    • Functional consequence of CD6Δd3 upregulation on T cell effector function untested
    • Whether CD6Δd3 acts as dominant negative unclear
  8. 2007 High

    Demonstration that CD6 ectodomain binds bacterial LPS and lipoteichoic acid with nanomolar affinity and that soluble CD6 protects mice from lethal endotoxemia revealed an innate immune pattern-recognition function for CD6 beyond adaptive T cell costimulation.

    Evidence Recombinant soluble CD6 binding assays, SPR affinity measurement (KD ~27 nM for LPS), in vivo LPS challenge with survival and cytokine readouts

    PMID:17601777

    Open questions at the time
    • Which SRCR domain binds LPS not mapped
    • Signaling pathway triggered by LPS–CD6 on T cells not dissected separately from TCR signals
    • Physiological relevance of CD6 pathogen sensing in infection models untested
  9. 2014 High

    Quantitative proteomics in primary T cells revealed that CD6 recruits SLP-76 and Vav1 independently of the canonical adaptor LAT, establishing CD6 as a LAT-independent TCR signaling node, while concurrent work identified SRSF1 and chromatin acetylation as regulators of CD6 exon 5 alternative splicing.

    Evidence Knock-in affinity-tag MS in primary mouse CD4+ T cells; ChIP for Pol II/acetylation and RIP for SRSF1 with HDAC inhibitor perturbation

    PMID:24584089 PMID:24890719

    Open questions at the time
    • How GADS fits into the LAT-independent pathway not yet shown
    • Whether Vav1 recruitment is direct or SLP-76-mediated unclear
    • Epigenetic regulation of CD6 splicing in disease states untested
  10. 2016 High

    CD6 knockout mouse analysis revealed that CD6 deficiency causes augmented initial TCR calcium signaling but reduced thymocyte numbers and impaired Treg function, establishing CD6 as a dual positive/negative modulator of T cell development and activation in vivo.

    Evidence CD6 KO mice with bone marrow chimeras, TCR-transgenic crosses, calcium flux, Treg suppression assays, collagen-induced arthritis model

    PMID:27377588

    Open questions at the time
    • Molecular basis of enhanced calcium signaling in CD6-deficient cells undefined
    • Mechanism of impaired Treg function unclear
    • Whether phenotype is ALCAM-dependent or CD318-dependent not addressed
  11. 2017 High

    Identification of CD318 as a second CD6 ligand, demonstration that bivalent GADS(Y629)/SLP-76(Y662) recruitment is required for costimulation, and CD6 KO protection from EAE with impaired T cell transendothelial migration collectively established CD6 as a multi-ligand receptor integrating costimulation with tissue infiltration.

    Evidence MS-based CD318 identification, CD318 KO EAE model, Y629F/Y662F mutagenesis in Jurkat and primary T cells, brain endothelial transmigration assays

    PMID:28209777 PMID:28289074 PMID:28760953

    Open questions at the time
    • Which CD6 domain binds CD318 not mapped
    • Relative contributions of ALCAM vs. CD318 to IS formation undefined
    • Transendothelial migration mechanism downstream of CD6 not molecularly dissected
  12. 2021 High

    CRISPR knock-in quantitative MS defined the full CD6 signalosome as containing both positive regulators (SLP-76, ZAP70, VAV1) and the negative regulator UBASH3A/STS-2, plus constitutive associations supporting transendothelial migration, resolving the paradox of CD6 serving as both costimulatory and inhibitory.

    Evidence CRISPR/Cas9 knock-in in primary mouse T cells with time-resolved quantitative MS after TCR stimulation

    PMID:33125054

    Open questions at the time
    • Mechanism by which UBASH3A counteracts CD6 costimulation unknown
    • Stoichiometry of positive vs. negative regulator recruitment not determined
    • Whether constitutive CD6 associations change during inflammation not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how UBASH3A-mediated negative regulation mechanistically opposes GADS/SLP-76 costimulation; which SRCR domain(s) bind CD318; how CD6 dual signaling is partitioned during thymic selection versus peripheral activation; and whether CD6Δd3 actively suppresses signaling or merely fails to engage the synapse.
  • UBASH3A inhibitory mechanism via CD6 uncharacterized
  • CD318 binding domain on CD6 unmapped
  • No structural model of full-length CD6 cytoplasmic domain with adaptors
  • Functional role of CD6Δd3 beyond failure to localize is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-168256 Immune System 6
Partners
ALCAMCD5CDCP1GADSSDCBPSLP76UBASH3AVAV1
Complex memberships
CD5-CD6 complexTCR/CD3 complex (recruited upon activation)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 CD6 is a type I integral membrane glycoprotein with an extracellular domain containing scavenger receptor cysteine-rich (SRCR) domains, and its cytoplasmic domain contains serine residues that are substrates for phosphorylation during T cell activation. cDNA cloning, COS cell transfection, RNA blot hybridization, phosphorylation assays The Journal of experimental medicine High 1919444
1989 CD6 (T12) is a 130 kDa glycoprotein on T cells that, when cross-linked with anti-CD3, delivers co-activating signals to CD4+ T cells via an IL-2-dependent pathway, and its activation is macrophage-dependent. In vitro T cell proliferation assays, IL-2R expression measurement, anti-IL-2R inhibition, anti-CD3 cross-linking Journal of immunology High 2794503
1989 CD6 is a monomeric 130 kDa glycoprotein under reducing conditions with intrachain disulfide bonds, is extensively N-glycosylated, and is serine-phosphorylated in activated T cells; two anti-CD6 mAbs recognizing distinct epitopes deliver different activation signals linked to different cofactor requirements (macrophages vs. PMA). Surface radiolabeling, immunoprecipitation, Western blot, biosynthetic labeling with tunicamycin, phosphorylation assays Molecular immunology High 2481822
1990 CD6 surface expression is regulated by phosphorylation: PKC activation rapidly converts an unphosphorylated 105 kDa form to a phosphorylated 130 kDa form without requiring new protein synthesis; this interconversion is reversible and alkaline phosphatase treatment converts the 130 kDa form back to 105 kDa. Surface 125I labeling, immunoprecipitation, 32P labeling, alkaline phosphatase treatment, PKC activator stimulation Journal of immunology High 2384666
1991 CD6 biosynthesis proceeds through an 88 kDa nascent polypeptide, an immature N-glycosylated 110 kDa intermediate, and a mature 130 kDa surface form bearing sulfated O-linked oligosaccharides; CD6 is phosphorylated in resting cells and can be hyperphosphorylated by PKC activators. Pulse-chase biosynthetic labeling, tunicamycin treatment, 32P labeling, immunoprecipitation The Journal of biological chemistry High 2016320
1993 CD6 cytoplasmic tyrosine residues become phosphorylated upon TCR/CD3 stimulation; co-crosslinking with CD4 produces the highest level of CD6 tyrosine phosphorylation, while co-crosslinking with CD2 also augments it, but crosslinking CD2, CD4, or CD28 alone does not phosphorylate CD6. Anti-phosphotyrosine immunoprecipitation, co-crosslinking of CD3 with CD2, CD4, or CD28 on primary T cells The Journal of experimental medicine High 7678115
1995 CD6 has a large cytoplasmic domain of 244 amino acids (previously underestimated) containing two proline-rich SH3-binding motifs, serine-threonine-rich repeats, PKC phosphorylation sites, and casein kinase-2 sites; alternatively spliced cytoplasmic isoforms exist in human peripheral blood lymphocytes. RT-PCR, cDNA cloning and sequencing, COS cell transfection, immunoprecipitation, SDS-PAGE European journal of immunology High 7589069
1995 ALCAM (CD166) is a CD6 ligand: COS cells expressing CD6 adhere to thymic epithelial cells, this adhesion is blocked by anti-CD6 mAb, and an ALCAM-Rg fusion protein binds specifically to CD6 transfectants; ALCAM-CD6 interaction mediates thymocyte–thymic epithelial cell adhesion. COS cell transfection, cell adhesion assays, antibody blocking, immunoglobulin fusion protein binding, cDNA cloning The Journal of experimental medicine High 7760007
1995 The membrane-proximal SRCR domain (domain 3) of CD6 contains the ALCAM binding site; mAbs binding to this domain preferentially block CD6-ALCAM binding. Domain-specific CD6-Rg fusion proteins, cell adhesion assays, antibody blocking experiments The Journal of biological chemistry High 7543097
1996 The amino-terminal Ig-like domain of ALCAM specifically binds the membrane-proximal (third) SRCR domain of CD6 in a 1:1 stoichiometry, representing the first characterized Ig-domain/SRCR-domain protein interaction. Truncated Ig fusion proteins, receptor-ligand binding assays, thrombin cleavage to produce monomeric domains, stoichiometry determination The Journal of biological chemistry High 8663238
1997 Three residues in the membrane-proximal SRCR domain (domain 3) of CD6, located in a region of low sequence conservation, when mutated abolish ALCAM binding without disrupting overall CD6 conformation (as shown by intact mAb binding); these are the first residues critical for SRCR domain-ligand interaction. Site-directed mutagenesis, binding assays with anti-CD6 mAbs, ALCAM binding assays Biochemistry High 9054570
1996 Residues critical for CD6 binding in ALCAM cluster on the predicted A'GFCC'C" face of ALCAM's N-terminal Ig domain, identified by targeted mutagenesis; this site is conserved across species. Targeted mutagenesis of ALCAM, CD6-ALCAM binding assays Biochemistry High 8823162
2004 CD6 interacts with CD166 (ALCAM) with a KD of 0.4–1.0 μM and fast off-rate; soluble monomeric CD6 or CD166 at concentrations blocking this interaction inhibit antigen-specific human T cell responses, demonstrating that extracellular CD6-CD166 engagement is required for optimal immune response. Surface plasmon resonance (SPR) kinetics, soluble protein inhibition of antigen-specific T cell proliferation assays European journal of immunology High 15048703
1997 CD6 gene is located on chromosome 11q13 near CD5 and CD20; it is encoded by at least 13 exons with each SRCR domain encoded by a separate exon; at least five cytoplasmic domain isoforms exist from alternative splicing of cytoplasmic exons. Genomic cloning, FISH, YAC library screening, RT-PCR, mRNA analysis Journal of immunology High 9013954
1997 CD6 cytoplasmic tyrosine residues Y629 and Y662 (the two C-terminal tyrosines) are critical for TCR-induced tyrosine phosphorylation; isoform CD6e lacking proline-rich motifs is not phosphorylated; Ca2+ mobilization by CD6/TCR co-ligation requires a membrane-proximal cytoplasmic region N-terminal to amino acid 555, distinct from the tyrosine phosphorylation region. Chimeric receptor expression, TCR cross-linking, anti-phosphotyrosine immunoprecipitation, Ca2+ flux measurement, site-directed mutagenesis European journal of immunology High 9394826
2004 CD6 physically associates with the TCR/CD3 complex (shown by co-immunoprecipitation, co-capping, and FRET); CD6 and ALCAM colocalize with TCR/CD3 at the central SMAC of the immunological synapse; soluble CD6 reduces T cell-APC conjugate formation and inhibits CD3-mediated T cell proliferation in a dose-dependent manner. Co-immunoprecipitation, co-capping, FRET, confocal microscopy of Ag-specific conjugates, proliferation inhibition assays Journal of immunology High 15294938
2002 CD5 and CD6 physically associate at the lymphocyte cell membrane, co-immunoprecipitate from Brij 96 detergent lysates independently of other surface receptors, and co-accumulate at the immunological synapse; this association is independent of the CD5 cytoplasmic region. Co-immunoprecipitation, FRET, co-capping, co-modulation experiments, imaging of T cell-APC conjugates The Journal of biological chemistry High 12473675
2003 CD6 (rat OX52) co-precipitates with CD5, and the CD5 fraction associated with CD6 is highly phosphorylated compared to CD5 associated with TCR or CD2; CD6 uniquely associates with Lck, Fyn, ZAP-70, and the Tec-family kinase Itk (not found in CD2/CD5/TCR complexes); Lck+Itk effectively phosphorylate CD5 cytoplasmic peptides. Immunoprecipitation, in vitro kinase assays with synthetic peptides, RT-PCR cloning of rat CD6 Journal of leukocyte biology High 12525577
2005 CD6 and ALCAM are actively recruited to the DC-T cell contact zone; ALCAM-blocking antibodies interfere with DC-T cell conjugate formation; CD6-ALCAM interactions are required during the proliferative phase of T cell response; CD6 cross-linking with CD3 enhances proliferation to levels similar to CD28 co-stimulation. Fluorescence microscopy of DC-T cell contacts, antibody blocking of conjugate formation, T cell proliferation assays with blocking antibodies and recombinant ALCAM-Fc, CD6/CD3 co-crosslinking Blood High 16352806
2005 The cytoplasmic tail of CD6 interacts with syntenin-1, a PDZ domain-containing scaffolding protein, through CD6's C-terminal sequence (-YDDISAA) and both PDZ domains of syntenin-1; syntenin-1 accumulates at CD6 caps and at the immunological synapse. Yeast two-hybrid screen, mutational analysis, pull-down assays, co-immunoprecipitation in mammalian cells, confocal microscopy Journal of immunology High 16034076
2006 CD6 ligation recruits the adaptor SLP-76 through phosphorylation-dependent binding to tyrosine 662 (Y662) in the CD6 cytoplasmic domain (KD = 0.5 μM at 37°C); this interaction mediates CD6 costimulation; Y662F mutation abolishes both SLP-76 binding and costimulation; CD6 and SLP-76 co-precipitate from normal human T cells. Phosphopeptide binding assay (SPR/equilibrium), co-precipitation from primary T cells, CD6 cytoplasmic mutant analysis in T cell hybridoma model Molecular and cellular biology High 16914752
2006 CD6 ligation (by mAbs or ALCAM-Fc) induces time- and dose-dependent activation of ERK1/2, p38, and JNK MAPK cascades in T cells; this requires the C-terminal cytoplasmic region of CD6 and Src tyrosine kinases; CD6 ligation activates AP-1 and c-Fos SRE transcription; synergistic effects occur with TCR/CD3 co-ligation. Western blot for phospho-MAPK, reporter gene assays (SRE-luciferase, AP-1-luciferase), Src kinase inhibitors, mAb and ALCAM-Fc stimulation Journal of immunology High 16818773
2007 A CD6 isoform lacking SRCR domain 3 (CD6Δd3), generated by exon 5 skipping, cannot localize to the immunological synapse (unlike full-length CD6), demonstrating that SRCR domain 3 (the ALCAM-binding domain) is required for CD6 targeting to the T cell-APC interface; CD6Δd3 is upregulated upon T cell activation. cDNA cloning, flow cytometry, confocal imaging of immunological synapse, RT-PCR at single-cell level, Western blot Journal of immunology High 17371992
2007 CD6 binds lipoteichoic acid (Gram-positive bacteria) and LPS (Gram-negative bacteria) through its ectodomain; the KD for LPS-CD6 interaction is ~2.69×10⁻⁸ M; membrane CD6 also retains LPS-binding ability and activates the MAPK signaling cascade upon LPS binding; recombinant soluble CD6 protects mice from lethal LPS challenge and reduces TNF-α, IL-6, and IL-1β. Binding assays with recombinant soluble CD6, bacterial aggregation, SPR/affinity measurement, MAPK activation assays, in vivo LPS challenge mouse model, serum cytokine measurement PNAS High 17601777
2011 CD6 significantly attenuates early and late TCR signaling: expression of CD6 (but not a cytoplasmic domain deletion mutant) reduces calcium mobilization and IL-2 release after superantigen or anti-CD3 stimulation; morpholino-mediated knockdown of CD6 enhances calcium signals; blocking CD6-CD166 interaction with anti-CD166 increases T cell proliferation, but anti-CD6 antibodies inhibit it. Single-cell calcium imaging, IL-2 ELISA, Jurkat overexpression of CD6 vs. cytoplasmic deletion mutant, morpholino knockdown in primary human T cells, antibody blocking proliferation assays European journal of immunology High 21956609
2014 Quantitative mass spectrometry of primary mouse T cells revealed that CD6 recruits SLP-76 and Vav1 independently of the LAT adaptor, constituting a LAT-independent TCR signaling hub; 112 high-confidence time-resolved protein interactions around Zap70, Lat, and SLP-76 were mapped. Knock-in affinity tag mass spectrometry (quantitative proteomics) in primary CD4+ T cells, time-resolved interaction mapping Nature immunology High 24584089
2015 X-ray crystal structures of CD6 (three SRCR domains) and CD166 (two N-terminal domains) reveal a nonlinear organization of consecutive SRCR domains; a disease-associated SNP in CD6 introduces a glycosylation site that sterically hinders the CD6/CD166 interaction; native MS shows competition between heterophilic CD6-CD166 and homophilic CD166-CD166 interactions. X-ray crystallography, native mass spectrometry, glycosylation site mutagenesis, binding assays Structure High 26146185
2014 ALCAM recruitment to adhesion sites and its membrane tether-anchoring propensity depend on actin cytoskeletal interactions; linking ALCAM to the actin cortex strengthens CD6-mediated cell adhesion and stiffens the cortex, forming a mechanical link between CD6 (on T cells) and the actin cortex (via ALCAM on DCs) at the immunological synapse. Single-cell force spectroscopy, TIRF microscopy, ALCAM cytoplasmic tail mutation constructs, actin cortex stiffness measurements Journal of cell science High 24496453
2014 T cell activation regulates CD6 alternative splicing (exon 5 skipping to produce CD6Δd3) through increased RNA Pol II occupancy and chromatin acetylation; the splicing factor SRSF1 binds CD6 intron 4 to promote exon 5 inclusion, and upon activation SRSF1 is downregulated and its recruitment to CD6 transcript is impaired by increased chromatin acetylation. Chromatin immunoprecipitation (ChIP) for RNA Pol II and acetylation, RNA immunoprecipitation (RIP) for SRSF1, histone deacetylase inhibitor experiments, RT-PCR Journal of immunology High 24890719
2017 CD6 cytoplasmic Y629 residue recruits the SH2 adaptor GADS; bivalent recruitment of a GADS/SLP-76 complex (at Y629 and Y662 respectively) is required for CD6 costimulation; both Y629F and Y662F mutations abolish costimulation in Jurkat and primary T cells. Biochemical pulldown, mutational analysis of Y629F and Y662F in Jurkat and primary T cells, T cell activation assays Molecular and cellular biology High 28289074
2017 CD318 is a CD6 ligand distinct from CD166: identified using mAb 3A11 immunoprecipitation and proteomics; CD318 KO mice are protected from experimental autoimmune encephalomyelitis (like CD6 KO mice); CD318 mediates CD6-dependent adhesion of T cells to synovial fibroblasts. Mass spectrometry protein identification, CD318 KO mouse EAE model, T cell adhesion assays to synovial fibroblasts, soluble CD318 chemotaxis assay PNAS High 28760953
2021 CRISPR/Cas9-based quantitative MS of primary mouse T cells defines the CD6 signalosome as comprising both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation; CD6 also associates constitutively (independently of TCR engagement) with proteins supporting T cell transendothelial migration. CRISPR/Cas9 knock-in in primary mouse T cells, quantitative mass spectrometry, TCR stimulation time-course The Journal of experimental medicine High 33125054
2016 CD6 deficiency in mice reduces CD4+ and CD8+ single-positive thymocyte numbers; CD6−/− double-positive thymocytes show increased Ca2+ mobilization to TCR cross-linking; bone marrow chimera experiments reveal a T cell-autonomous selective disadvantage of CD6−/− cells during development; CD6−/− mice show increased effector/memory and regulatory T cells but diminished Treg suppressive activity. CD6 KO mouse analysis, bone marrow chimeras, TCR-transgenic crosses, Ca2+ flux assays, Treg suppression assays, collagen-induced arthritis model The Journal of experimental medicine High 27377588
2017 CD6 KO mice show decreased pathogenic T cell responses, reduced spinal cord T cell infiltration, and attenuated EAE; CD6-deficient T cells show augmented initial activation but reduced survival and proliferation, leading to decreased Th1 and Th17 polarization; activated CD6-deficient T cells show impaired infiltration through brain microvascular endothelial cell monolayers. CD6 KO mouse EAE model, T cell recall assays, Th1/Th17 polarization assays, transendothelial migration assay, CD6-humanized mouse treatment with anti-human CD6 mAb PNAS High 28209777
1997 CD6 ligation protects chronic lymphocytic leukemia B cells from anti-IgM-induced apoptosis by downregulating bax-α mRNA levels and preventing bcl-2 downregulation, resulting in an increased Bcl-2/Bax ratio. Anti-CD6 crosslinking on B-CLL cells, Northern blot for bax-α and bcl-2 mRNA, apoptosis assays Blood Medium 9108402
2014 CD6 and CD166/ALCAM interact with Galectin-1 and Galectin-3 in a carbohydrate-dependent manner; galectins interfere with superantigen-induced T cell proliferation and CD6-CD166-mediated cell adhesion; CD6 expression protects cells from galectin-induced apoptosis. Galectin binding assays, T cell proliferation assays with galectin addition, cell adhesion assays, apoptosis measurement FEBS letters Medium 24945728
2016 CD6 is selectively expressed on B1 cells outside the bone marrow and peritoneal cavity; CD6−/− mice are protected from intestinal ischemia/reperfusion injury, with reduced natural IgM titers and B1a cell populations, demonstrating a role for CD6 in B1a cell self-renewal. CD6 KO mouse intestinal I/R model, flow cytometry for B1a cells, serum natural IgM ELISA The Journal of biological chemistry Medium 27909060
1994 PKC activation by phorbol ester (PMA) increases CD6 surface expression by increasing CD6 mRNA transcription (nuclear run-on); this requires new protein synthesis; CD2 ligation (but not ligation of other surface molecules tested) upregulates CD6 expression on thymocytes but not mature T cells. Northern blot, nuclear run-on transcription assays, Western blot, flow cytometry, PKC inhibitor studies, actinomycin D and cycloheximide experiments Journal of immunology High 8207228
2004 A second CD6 ligand (3A11 antigen, later identified as CD318) distinct from CD166 is expressed on cells from thymus, skin, synovium, and cartilage; its expression is enhanced by IFN-γ; it has a molecular mass of 130 kDa and is immunoprecipitated by soluble CD6-Ig fusion protein; anti-CD166 siRNA knockdown does not alter 3A11 expression. Immunoprecipitation with CD6-Ig fusion protein, confocal microscopy, siRNA knockdown of CD166, flow cytometry, T cell adhesion assays Journal of immunology Medium 15528349
2017 Itolizumab (anti-CD6 D1 mAb) directly inhibits CD6 receptor hyperphosphorylation and decreases associated ZAP70 kinase and SLP76 docking protein levels; F(ab')2 fragment of Itolizumab does not produce this inhibition, indicating the intact antibody format is required for the mechanism. CD6 phosphorylation Western blot, ZAP70 and SLP76 co-immunoprecipitation, Itolizumab vs. F(ab')2 comparison PloS one Medium 28672038

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature genetics 638 19525953
1995 Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand. The Journal of experimental medicine 325 7760007
2005 Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells. Blood 177 16352806
1991 The lymphocyte glycoprotein CD6 contains a repeated domain structure characteristic of a new family of cell surface and secreted proteins. The Journal of experimental medicine 154 1919444
1995 Identification and characterization of a 100-kD ligand for CD6 on human thymic epithelial cells. The Journal of experimental medicine 129 7535342
1997 CD6-ligand interactions: a paradigm for SRCR domain function? Immunology today 124 9357143
2004 Frontline: Optimal T cell activation requires the engagement of CD6 and CD166. European journal of immunology 122 15048703
1992 Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 121 1607923
2004 Relevance of CD6-mediated interactions in T cell activation and proliferation. Journal of immunology (Baltimore, Md. : 1950) 120 15294938
1990 Natural history of mixed chimerism after bone marrow transplantation with CD6-depleted allogeneic marrow: a stable equilibrium. Blood 119 1967216
2014 Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub. Nature immunology 104 24584089
2007 CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock. Proceedings of the National Academy of Sciences of the United States of America 102 17601777
2022 The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. The Journal of clinical investigation 87 34981775
1989 Anti-T12, an anti-CD6 monoclonal antibody, can activate human T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 85 2794503
1990 Reconstitution of T-cell function after CD6-depleted allogeneic bone marrow transplantation. Blood 84 1970938
1997 CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM. Blood 83 9108402
1995 The membrane-proximal scavenger receptor cysteine-rich domain of CD6 contains the activated leukocyte cell adhesion molecule binding site. The Journal of biological chemistry 82 7543097
2017 CD318 is a ligand for CD6. Proceedings of the National Academy of Sciences of the United States of America 81 28760953
2006 CD6 regulates T-cell responses through activation-dependent recruitment of the positive regulator SLP-76. Molecular and cellular biology 80 16914752
1996 The amino-terminal immunoglobulin-like domain of activated leukocyte cell adhesion molecule binds specifically to the membrane-proximal scavenger receptor cysteine-rich domain of CD6 with a 1:1 stoichiometry. The Journal of biological chemistry 78 8663238
2017 CD6 as a potential target for treating multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America 77 28209777
1997 Characterization of mouse ALCAM (CD166): the CD6-binding domain is conserved in different homologs and mediates cross-species binding. European journal of immunology 76 9209500
2016 CD6 modulates thymocyte selection and peripheral T cell homeostasis. The Journal of experimental medicine 75 27377588
2011 CD6 attenuates early and late signaling events, setting thresholds for T-cell activation. European journal of immunology 71 21956609
2011 The CD6 multiple sclerosis susceptibility allele is associated with alterations in CD4+ T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 69 21849685
2011 Antioxidative potential of folate producing probiotic Lactobacillus helveticus CD6. Journal of food science and technology 69 24425884
2000 Cell surface receptors and their ligands: in vitro analysis of CD6-CD166 interactions. Proteins 69 10861932
1992 Bromelain treatment of human T cells removes CD44, CD45RA, E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 surface molecules and markedly enhances CD2-mediated T cell activation. Journal of immunology (Baltimore, Md. : 1950) 68 1281188
2010 CD6 synergistic co-stimulation promoting proinflammatory response is modulated without interfering with the activated leucocyte cell adhesion molecule interaction. Clinical and experimental immunology 65 20726988
1997 CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission. Blood 65 9108425
2015 Structures of CD6 and Its Ligand CD166 Give Insight into Their Interaction. Structure (London, England : 1993) 62 26146185
1993 Tyrosine phosphorylation of CD6 by stimulation of CD3: augmentation by the CD4 and CD2 coreceptors. The Journal of experimental medicine 61 7678115
1993 Activation of human T cells through CD6: functional effects of a novel anti-CD6 monoclonal antibody and definition of four epitopes of the CD6 glycoprotein. International immunology 61 7690243
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