Affinage

CD6

T-cell differentiation antigen CD6 · UniProt P30203

Length
668 aa
Mass
71.8 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 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

CD6 is a type I transmembrane glycoprotein expressed predominantly on T cells that functions as a co-receptor at the immunological synapse, fine-tuning T cell activation, thymocyte selection, and effector differentiation (PMID:1919444, PMID:15294938, PMID:27377588). Its three extracellular SRCR domains mediate ligand recognition: the membrane-proximal SRCR domain 3 binds the N-terminal Ig domain of CD166/ALCAM with a defined interface and 1:1 stoichiometry and micromolar, fast-off-rate affinity, an interaction that competes with ALCAM homophilic binding and is structurally constrained by a multidomain SRCR organization (PMID:7760007, PMID:7543097, PMID:8663238, PMID:15048703, PMID:26146185). CD318 is a second, distinct CD6 ligand that supports T cell adhesion and chemotaxis and, like CD6 itself, is required for autoimmune encephalomyelitis pathology (PMID:28760953, PMID:15528349). CD6 physically associates with the TCR/CD3 complex and partitions to the central supramolecular activation cluster, where ligand engagement provides CD3/CD28-comparable costimulation and stabilizes T cell–APC conjugates (PMID:15294938, PMID:16352806). Upon TCR engagement its 244-residue cytoplasmic tail is tyrosine-phosphorylated on Y629 and Y662, which respectively recruit GADS and SLP-76 as a bivalent complex; this hub also assembles ZAP70 and VAV1 to drive costimulation independently of the LAT adaptor, while simultaneously recruiting the negative regulator UBASH3A/STS-2, explaining how CD6 both amplifies and restrains activation and engages MAPK (ERK/p38/JNK) and AP-1 outputs (PMID:9394826, PMID:16914752, PMID:24584089, PMID:33125054, PMID:28289074, PMID:16818773). CD6 output is gated by activation-induced alternative splicing in which SRSF1 normally promotes exon 5 inclusion but is displaced upon activation-linked chromatin acetylation, generating a domain 3–deleted isoform that cannot bind ALCAM or localize to the synapse (PMID:17371992, PMID:24890719). Genetically, a multiple sclerosis–associated CD6 allele reduces full-length CD6 by lowering exon 5 expression and diminishes long-term CD4+ T cell proliferation, and CD6 deficiency reduces post-activation T cell survival, Th1/Th17 polarization, and transendothelial migration (PMID:21849685, PMID:28209777, PMID:27377588).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1991 High

    Establishing CD6 as a type I membrane glycoprotein with three extracellular SRCR domains and a phosphorylatable cytoplasmic tail defined the architecture on which all later signaling and ligand work was built.

    Evidence cDNA cloning and COS cell expression with biochemical phosphorylation analysis

    PMID:1919444 PMID:2016320 PMID:2384666 PMID:2481822

    Open questions at the time
    • Cytoplasmic signaling partners not yet identified
    • Ligand identity unknown at this stage
  2. 1995 High

    Discovery that the long 244-residue cytoplasmic domain (initially mis-assigned as short due to splicing) contains SH3-binding and kinase phosphorylation motifs reframed CD6 as a signaling co-receptor rather than a simple adhesion molecule.

    Evidence Full-length cDNA isolation, sequence analysis, transfection confirmation

    PMID:7589069

    Open questions at the time
    • Direct cytoplasmic effectors not yet bound
    • Functional consequence of motifs untested
  3. 1996 High

    Identification of ALCAM/CD166 as the CD6 ligand and mapping the interaction to SRCR domain 3 / the ALCAM N-terminal Ig domain established the molecular basis for CD6-mediated cell adhesion.

    Evidence Reciprocal fusion-protein binding, domain-specific constructs, mutagenesis, and stoichiometry determination

    PMID:7543097 PMID:7760007 PMID:8663238 PMID:8823162 PMID:9054570

    Open questions at the time
    • Affinity/kinetics not yet quantified
    • Functional role of adhesion in T cell responses not defined
  4. 1997 High

    Showing that TCR/CD3 crosslinking drives CD6 cytoplasmic tyrosine phosphorylation at Y629/Y662 and that this is separable from Ca2+ signaling connected CD6 directly into proximal TCR signaling.

    Evidence Anti-phosphotyrosine IP after CD3 crosslinking and chimeric receptor point/truncation mutants with Ca2+ flux readout

    PMID:7678115 PMID:9013954 PMID:9394826

    Open questions at the time
    • Adaptors recruited to phospho-tyrosines unidentified
    • Link between phosphorylation and downstream transcription unclear
  5. 2005 High

    Demonstration that CD6 associates with the TCR/CD3 complex, localizes to the central SMAC, and that CD6-ALCAM engagement provides costimulation and stabilizes DC–T conjugates positioned CD6 at the heart of the immunological synapse.

    Evidence Co-IP, co-capping, FRET, confocal imaging of T-APC conjugates, antibody blocking, and proliferation/reporter assays

    PMID:12473675 PMID:12525577 PMID:15048703 PMID:15294938 PMID:16352806

    Open questions at the time
    • Whether CD6 is net activating or inhibitory remained unresolved
    • Itk-CD6 association reported by a single lab
  6. 2006 High

    Identifying SLP-76 as a direct phospho-Y662 partner and showing CD6 ligation activates ERK/p38/JNK and AP-1 defined a concrete costimulatory signaling output.

    Evidence Phosphopeptide binding with Kd, co-IP from primary T cells, Y662F mutant, MAPK phospho-blot with Src inhibitors and reporter assays

    PMID:16034076 PMID:16818773 PMID:16914752

    Open questions at the time
    • Role of the second tyrosine Y629 not defined
    • How signaling integrates with TCR proximal machinery unclear
  7. 2011 High

    Genetic and functional dissection of an MS-associated CD6 allele and CD6 knockdown revealed CD6 can attenuate early TCR signaling yet sustain long-term proliferation, exposing its dual regulatory nature.

    Evidence Genotype-stratified flow cytometry, exon-specific siRNA, Ca2+ flux, IL-2 ELISA, proliferation assays in Jurkat and primary T cells

    PMID:21849685 PMID:21956609

    Open questions at the time
    • Molecular basis reconciling attenuation vs. costimulation not resolved
    • In vivo relevance of dual signaling untested
  8. 2014 High

    Quantitative signalosome MS and splicing studies showed CD6 forms a LAT-independent hub recruiting SLP-76/Vav1/ZAP70 and that SRSF1-controlled exon 5 splicing gates ligand binding and synapse targeting.

    Evidence Knock-in affinity-tagged MS in primary T cells, ChIP/RNA-IP, HDAC inhibitor treatment, isoform imaging

    PMID:17371992 PMID:24584089 PMID:24890719 PMID:24945728

    Open questions at the time
    • Negative regulators of the hub not yet identified
    • Trigger linking activation to chromatin acetylation incompletely defined
  9. 2016 High

    Knockout mouse genetics established T cell-intrinsic roles for CD6 in thymocyte selection, regulatory T cell function, and B1a cell homeostasis, moving CD6 from in vitro signaling into developmental and disease physiology.

    Evidence CD6-/- mice with TCR-transgenic crosses, bone marrow chimeras, Treg suppression assays, intestinal I/R model

    PMID:27377588 PMID:27909060

    Open questions at the time
    • Mechanism of CD6 control of B1a self-renewal not biochemically resolved
    • Signaling basis of selection defect unclear
  10. 2017 High

    Identification of CD318 as a bona fide second ligand, definition of the bivalent GADS(Y629)/SLP-76(Y662) costimulatory module, and demonstration of CD6's role in T cell survival/Th17 differentiation and migration consolidated CD6 as an autoimmunity-relevant co-receptor and therapeutic target.

    Evidence CD318 KO in EAE, adhesion/chemotaxis assays, Y629F/Y662F mutants, CD6-/- T cell transfer and migration assays, anti-CD6 (itolizumab) signaling blockade

    PMID:15528349 PMID:28209777 PMID:28289074 PMID:28672038 PMID:28760953

    Open questions at the time
    • Mechanism by which domain 1 antibody causes CD6 dephosphorylation not fully resolved
    • Relative contributions of ALCAM vs. CD318 in disease not dissected
  11. 2021 High

    Comprehensive CRISPR-based signalosome mapping revealed CD6 simultaneously recruits positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators plus constitutive migration-associated partners, providing a unified explanation for CD6's bidirectional control of T cell activation.

    Evidence CRISPR/Cas9 knock-in of tagged proteins and quantitative MS in primary mouse T cells compared with LAT and CD5 signalosomes

    PMID:33125054

    Open questions at the time
    • How positive vs. negative outputs are balanced contextually unknown
    • Structural basis of UBASH3A recruitment undetermined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD6 dynamically switches between amplifying and attenuating TCR signaling in specific T cell subsets and disease contexts, and the in vivo significance of its non-T-cell expression, remain open.
  • No structural model of the assembled cytoplasmic signalosome
  • Functional role of CD6 in brain cells uncharacterized
  • Quantitative balance of ALCAM vs. CD318 signaling in vivo unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 4 GO:0060090 molecular adaptor activity 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 1
Partners
ALCAMCD318CD5GADSSLP-76UBASH3AVAV1ZAP70
Complex memberships
CD6 signalosomeTCR/CD3 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 CD6 is a type I integral membrane protein with three extracellular SRCR (scavenger receptor cysteine-rich) domains. The cytoplasmic domain contains serine residues that are substrates for phosphorylation during T cell activation. cDNA cloning, COS cell transfection, RNA blot hybridization, sequence analysis The Journal of experimental medicine High 1919444
1989 CD6 is a 130 kDa monomeric glycoprotein with intrachain disulfide bonds that is serine-phosphorylated in activated T cells and contains a protease-sensitive site. Two distinct epitopes (recognized by anti-T12 and anti-2H1) convey different T cell activation signals. Surface radiolabeling, immunoprecipitation, Western blot, SDS-PAGE under reducing/non-reducing conditions Molecular immunology High 2481822
1990 CD6 exists as two molecular forms in dynamic equilibrium: an unphosphorylated 105 kDa form in resting T cells that rapidly converts to a phosphorylated 130 kDa form upon PKC activation or serum exposure. Alkaline phosphatase treatment of the 130 kDa form converts it back to the 105 kDa form, demonstrating the conversion is phosphorylation-dependent. Surface 125I-labeling, immunoprecipitation, 32P metabolic labeling, alkaline phosphatase treatment, pulse-chase experiments Journal of immunology High 2384666
1991 CD6 undergoes N-glycosylation (nascent polypeptide 88 kDa → immature N-glycosylated form 110 kDa → mature surface form 130 kDa after addition of sulfated O-linked oligosaccharide) and is phosphorylated on serine in resting cells with hyperphosphorylation by PKC activators. Concanavalin A-activated cells are phosphorylated at additional site(s). Pulse-chase biosynthetic labeling, tunicamycin treatment, 32P-labeling, immunoprecipitation The Journal of biological chemistry High 2016320
1993 CD6 cytoplasmic tyrosine residues are phosphorylated upon T cell activation via TCR/CD3 crosslinking. Co-crosslinking CD3 with CD4 produces the highest CD6 tyrosine phosphorylation, whereas crosslinking CD2, CD4, or CD28 alone does not phosphorylate CD6. Anti-phosphotyrosine immunoprecipitation, T cell stimulation assays with anti-CD3/CD2/CD4/CD28 crosslinking The Journal of experimental medicine High 7678115
1995 ALCAM (CD166) is a CD6 ligand expressed on thymic epithelial cells. COS cells expressing CD6 adhere to thymic epithelial cells; a CD6-immunoglobulin fusion protein binds ALCAM-transfected COS cells; and ALCAM-Rg fusion protein binds CD6-expressing COS cells, establishing bidirectional CD6-ALCAM interaction. COS cell transfection, cell adhesion assays, immunoglobulin fusion protein binding assays, cDNA cloning, antibody blocking The Journal of experimental medicine High 7760007
1995 The membrane-proximal SRCR domain (domain 3) of CD6 contains the ALCAM binding site. Domain-specific CD6-Rg fusion proteins showed that only those containing the third (membrane-proximal) SRCR domain bind ALCAM, and mAbs binding this domain preferentially block CD6-ALCAM binding. Domain-specific CD6 immunoglobulin fusion proteins in cell adhesion assays, antibody blocking experiments The Journal of biological chemistry High 7543097
1996 The amino-terminal Ig-like domain of ALCAM binds specifically to the third membrane-proximal SRCR domain of CD6 with 1:1 stoichiometry, as determined using thrombin-cleaved single-domain fusion proteins in binding assays. Truncated immunoglobulin fusion proteins, receptor-ligand binding assays, stoichiometry determination The Journal of biological chemistry High 8663238
1997 Three residues in the membrane-proximal SRCR domain of CD6 (in a region of low sequence conservation) are critical for ALCAM binding; mutating these residues abolishes ligand binding without affecting binding of conformationally sensitive anti-CD6 mAbs, demonstrating a defined binding interface. Site-directed mutagenesis of CD6D3, ALCAM binding assays, anti-CD6 mAb panel binding Biochemistry High 9054570
1996 The CD6 binding site on ALCAM maps to residues on the predicted A'GFCC'C" beta-sheet face of its N-terminal Ig domain, as determined by targeted mutagenesis. This site is conserved across species, and non-conserved residues map to the opposite face. Targeted mutagenesis of ALCAM, CD6 binding assays Biochemistry High 8823162
1995 Human CD6 possesses a 244-amino acid cytoplasmic domain (confirmed by cDNA isolation) containing two proline-rich SH3 domain-binding motifs, a serine-threonine-rich repeated motif, PKC phosphorylation sites, and casein kinase-2 phosphorylation sites. Previously reported short cytoplasmic domain resulted from a frame-shift due to alternative splicing. RT-PCR, cDNA cloning, sequence analysis, transfection/immunoprecipitation confirmation European journal of immunology High 7589069
1997 The two C-terminal tyrosine residues (Y629 and Y662) in the CD6 cytoplasmic domain are critical for tyrosine phosphorylation following TCR crosslinking. CD6 isoform CD6e (lacking proline-rich motifs) is not phosphorylated. All CD6 isoforms including CD6e can increase intracellular Ca2+ upon CD6/TCR co-ligation through a region N-terminal of amino acid 555. Chimeric receptor constructs (extracellular mouse CD6 + human CD6 cytoplasmic variants), stable expression, anti-phosphotyrosine Western blot, intracellular Ca2+ flux measurement European journal of immunology High 9394826
2006 CD6 costimulation is mediated through the phosphorylated cytoplasmic tyrosine Y662, which directly recruits the adaptor SLP-76. A direct interaction between SLP-76 and a phosphorylated CD6 peptide (Kd = 0.5 μM at 37°C) was demonstrated, and co-precipitation of SLP-76 with CD6 was shown in normal human T cells. CD6 mutant Y662F abolishes both costimulation and SLP-76 interaction. Phosphopeptide binding assay (Kd measurement), co-immunoprecipitation from primary T cells, CD6 Y662F mutant analysis in T-cell hybridoma Molecular and cellular biology High 16914752
2004 CD6 physically associates with the TCR/CD3 complex (shown by co-immunoprecipitation, co-capping, and FRET). CD6 and its ligand CD166/ALCAM co-localize with TCR/CD3 at the central SMAC of the immunological synapse. Soluble recombinant CD6 reduces Ag-specific T-APC conjugate formation and inhibits CD3-mediated T cell proliferation in a dose-dependent manner. Co-immunoprecipitation, co-capping, FRET, confocal microscopy of antigen-specific T-APC conjugates, proliferation assays with soluble rCD6 Journal of immunology High 15294938
2005 CD6-ALCAM interactions are actively recruited to the antigen-induced DC-T cell contact zone and are required for stable DC-T cell conjugate formation and for sustained T cell proliferation. CD6-ALCAM engagement provides costimulatory signals comparable to CD3/CD28 co-crosslinking when CD6 and CD3 are simultaneously crosslinked. Fluorescence microscopy of DC-T cell contacts, antibody blocking of ALCAM or CD6, proliferation assays, reporter gene assays for transcriptional activity Blood High 16352806
2004 CD6 binds CD166 (ALCAM) with Kd = 0.4–1.0 μM and fast off-rate (Koff ≥ 0.4–0.63 s−1), while CD166 homophilic interaction has ~100-fold lower affinity (Kd = 29–48 μM). Soluble monomeric CD6 and CD166 at concentrations blocking the CD6/CD166 interaction inhibit antigen-specific human T cell responses. Surface plasmon resonance/kinetic binding assays, human T cell antigen-specific proliferation inhibition with soluble monomeric proteins European journal of immunology High 15048703
2006 CD6 ligation (with anti-CD6 mAbs or ALCAM-Fc) induces time- and dose-dependent activation of ERK1/2, p38, and JNK MAPK cascades in T cells. The C-terminal cytoplasmic region of CD6 and Src tyrosine kinases are required for CD6-induced ERK1/2 activation. CD6 ligation also activates c-Fos/AP-1 transcription, and CD6/TCR co-ligation is synergistic. Phospho-specific Western blot for MAPK activation, cytoplasmic deletion mutants, Src kinase inhibitors, reporter gene assays (SRE/AP-1) Journal of immunology High 16818773
2002 CD5 and CD6 physically associate at the lymphocyte cell membrane (co-immunoprecipitation from Brij 96 but not NP-40 lysates), and both co-localize at the immunological synapse. This association is independent of co-expression of other lymphocyte receptors and the integrity of the CD5 cytoplasmic region. Co-immunoprecipitation, FRET, co-capping, co-modulation experiments, confocal microscopy of T cell-APC conjugates The Journal of biological chemistry High 12473675
2003 CD6 (rat homolog OX52) co-precipitates with CD5, and the fraction of CD5 associated with CD6 is highly phosphorylated in kinase assays. CD6 associates with Lck, Fyn, ZAP-70, and uniquely with the Tec-family kinase Itk (absent from CD2, CD5, TCR complexes). Lck together with Itk effectively phosphorylates CD5 cytoplasmic peptides, suggesting CD6 regulates CD5 tyrosine phosphorylation. Immunoprecipitation, in vitro kinase assays with synthetic peptides, Western blot Journal of leukocyte biology Medium 12525577
2005 Syntenin-1, a PDZ domain-containing scaffolding protein, interacts with the cytoplasmic tail of CD6 through the C-terminal sequence -YDDISAA of CD6 and both PDZ domains of syntenin-1. This interaction was confirmed by yeast two-hybrid, pull-down, and co-immunoprecipitation; syntenin-1 accumulates at CD6 caps and at the immunological synapse. Yeast two-hybrid screening, pull-down assays, co-immunoprecipitation, mutational analysis, confocal microscopy Journal of immunology High 16034076
2007 CD6 binds to pathogen-associated molecular patterns including lipoteichoic acid (Gram-positive bacteria) and LPS (Gram-negative bacteria). The Kd of the LPS-rsCD6 interaction is 2.69 × 10−8 M. Membrane CD6 also retains LPS-binding ability and activates the MAPK signaling cascade. Recombinant soluble CD6 administration before lethal LPS challenge significantly improves mouse survival and reduces TNF-α, IL-6, and IL-1β levels. Binding assays with recombinant soluble CD6, Kd determination, bacterial aggregation assays, MAPK activation Western blot, in vivo LPS challenge with survival endpoint and cytokine ELISA Proceedings of the National Academy of Sciences of the United States of America High 17601777
2007 An alternative CD6 isoform (CD6Δd3), resulting from exon 5 skipping (loss of SRCR domain 3), lacks the CD166 binding domain and fails to localize at the immunological synapse during antigen presentation, whereas full-length CD6 (with domain 3) targets to the immunological synapse. CD6Δd3 is markedly upregulated upon T cell activation. RT-PCR cloning of isoforms, immunoblotting, flow cytometry with domain-specific antibodies, live confocal microscopy of T cell-APC contacts, single-cell RT-PCR Journal of immunology High 17371992
2014 T cell activation regulates CD6 alternative splicing (exon 5 skipping producing CD6Δd3) through increased RNA Pol II occupancy and chromatin acetylation. The splicing factor SRSF1 binds to a regulatory element in CD6 intron 4 and promotes exon 5 inclusion; SRSF1 is downregulated upon T cell activation and its recruitment to the CD6 transcript is impaired by increased chromatin acetylation. Chromatin immunoprecipitation (RNA Pol II and histone acetylation), RT-PCR of splice variants, HDAC inhibitor treatment, RNA immunoprecipitation of SRSF1 Journal of immunology High 24890719
2014 Quantitative mass spectrometry of primary CD4+ T cell signalosomes shows that CD6 recruits SLP-76 and the GEF Vav1 independently of the LAT adaptor, constituting a LAT-independent TCR signaling hub. CD6 also recruits ZAP70 to its signalosome. Knock-in affinity-tagged proteins in primary mouse T cells, quantitative MS of co-purified complexes (time-resolved), comparison between LAT-present and LAT-absent conditions Nature immunology High 24584089
2011 CD6 expression alone (without ligand engagement) attenuates early TCR signaling (Ca2+ mobilization) and late responses (IL-2 release). Removal of the cytoplasmic domain of CD6 abolishes this inhibitory effect. Knockdown of CD6 by morpholino enhanced anti-CD3-induced Ca2+ signals in primary human T cells. CD6-CD166 interaction blocking with anti-CD166 antibodies increased T cell proliferation, while anti-CD6 antibodies decreased it. Single-cell Ca2+ flux measurements, Jurkat cells expressing human CD6 vs. CD6 cytoplasmic deletion mutant, morpholino CD6 knockdown in primary human T cells, IL-2 ELISA, proliferation assays European journal of immunology High 21956609
2015 Crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166 were solved by X-ray crystallography. The structure reveals a nonlinear organization of consecutive SRCR domains. An MS-associated SNP in CD6 causes glycosylation that sterically hinders the CD6/CD166 interaction. Native mass spectrometry showed competition between CD6/CD166 heterophilic and CD166/CD166 homophilic interactions. X-ray crystallography, native mass spectrometry, SNP glycosylation analysis Structure High 26146185
2017 CD318 is a second CD6 ligand distinct from CD166/ALCAM. CD318 KO mice, like CD6 KO mice, are protected in experimental autoimmune encephalomyelitis. CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. Soluble CD318 is chemoattractive to T cells. Identification by mAb 3A11, CD318 KO mouse in EAE model, T cell adhesion assays to synovial fibroblasts, CD6-CD318 binding assays, chemotaxis assay Proceedings of the National Academy of Sciences of the United States of America High 28760953
2017 CD6-deficient T cells exhibit augmented initial activation but significantly reduced survival and proliferation after activation, leading to decreased Th1 and Th17 polarization. CD6-deficient activated T cells show impaired migration through brain microvascular endothelial cell monolayers. CD6 is thus a positive regulator of activated T cell survival/proliferation and infiltration. CD6 KO mice in EAU/EAE model, adoptive transfer of CD6-/- T cells, in vitro transendothelial migration assay, T cell differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 28209777
2016 CD6 modulates thymocyte selection: CD6-/- thymi show reduced CD4+ and CD8+ single-positive subsets; double-positive thymocytes show increased Ca2+ mobilization upon TCR crosslinking; and CD6-/- T cells have a T cell-autonomous selective disadvantage during development confirmed by bone marrow chimeras. CD6-/- mice display increased regulatory T cell frequencies but with diminished suppressive activity. CD6-/- mice with TCR-transgenic crosses (OT-I, Marilyn), bone marrow chimeras, Ca2+ flux measurement, T reg suppression assays, collagen-induced arthritis model The Journal of experimental medicine High 27377588
2021 The CD6 signalosome, mapped by CRISPR/Cas9-based quantitative MS in primary mouse T cells, contains both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. CD6 also associates constitutively (TCR-independent) with proteins involved in T cell transendothelial migration. UBASH3A (STS-2) is identified as a component of the CD6 signalosome. CRISPR/Cas9 knock-in of tagged proteins in primary mouse T cells, quantitative mass spectrometry of CD6 signalosome, comparison with LAT and CD5 signalosomes The Journal of experimental medicine High 33125054
2017 CD6 costimulation requires bivalent recruitment of a GADS/SLP-76 complex: the SH2 domain of GADS binds phosphorylated Y629 of CD6, and SLP-76 binds phosphorylated Y662. Both Y629F and Y662F mutations abolish costimulation by CD6 in human Jurkat and primary T cells. Biochemical interaction mapping (SH2 domain binding), CD6 Y629F and Y662F mutant analysis, Jurkat and primary T cell functional assays Molecular and cellular biology High 28289074
1997 CD6 ligation (with anti-CD6 antibody) protects CLL B cells from anti-IgM-induced apoptosis by downregulating bax-alpha mRNA and maintaining bcl-2 mRNA levels, resulting in an increased Bcl-2/Bax ratio. Anti-CD6 crosslinking of CLL B cells, flow cytometry for apoptosis, Northern blot for bax and bcl-2 mRNA Blood Medium 9108402
2014 CD6 interacts with Galectin-1 and Galectin-3 in a carbohydrate-dependent manner. This interaction interferes with superantigen-induced T cell proliferation and cell adhesion mediated by CD6-CD166/ALCAM. CD6 expression protects cells from galectin-induced apoptosis. Co-immunoprecipitation/pull-down, proliferation assays, cell adhesion assays, apoptosis assays with galectin treatment FEBS letters Medium 24945728
2014 Dynamic coupling of ALCAM to the actin cortex (through intracellular adaptor proteins) strengthens CD6-ALCAM cell adhesion bonds and stiffens the cortex, but does not influence the intrinsic affinity of CD6-ALCAM bonds. ALCAM recruitment to adhesion sites and membrane tether formation depend on actin cytoskeletal interactions. Single-cell force spectroscopy combined with TIRF microscopy, ALCAM cytoplasmic tail mutants expressed in ALCAM-expressing cells Journal of cell science High 24496453
2011 The MS susceptibility allele in CD6 (rs17824933) is associated with decreased expression of full-length CD6 in CD4+ and CD8+ T cells due to underexpression of exon 5 (which encodes the ALCAM binding domain), and this leads to diminished long-term proliferation of CD4+ T cells. siRNA knockdown of full-length CD6 recapitulates the proliferation defect. Flow cytometry for CD6 protein levels in primary T cells stratified by genotype, exon-specific siRNA knockdown, long-term proliferation assay Journal of immunology High 21849685
2004 A second CD6 ligand (the 3A11 antigen, later identified as CD318) distinct from CD166/ALCAM is expressed on cells derived from thymus, skin, synovium, and cartilage, and is enhanced by IFN-γ. Soluble CD6-Ig fusion protein immunoprecipitates the 130 kDa 3A11 antigen, and it is not reduced by CD166-specific siRNA knockdown, confirming it is a distinct ligand. Flow cytometry, immunoprecipitation with CD6-Ig fusion protein, confocal microscopy, CD166 siRNA knockdown, T cell adhesion inhibition assay Journal of immunology High 15528349
2016 CD6 regulates intestinal ischemia/reperfusion injury by controlling the self-renewal of B1a cells outside of the peritoneal cavity. CD6 is selectively expressed on B1 cells outside bone marrow and peritoneum; CD6-/- mice have reduced B1a cell populations and decreased pathogenic natural IgM titers, resulting in protection from intestinal I/R injury. CD6-/- mice in intestinal I/R model, flow cytometry of B1a cell populations, natural IgM ELISA, histopathology The Journal of biological chemistry Medium 27909060
2017 Itolizumab (anti-CD6 domain 1 mAb) directly inhibits CD6 receptor hyperphosphorylation upon TCR activation and decreases associated ZAP70 kinase and SLP-76 docking protein levels. It also reduces T cell differentiation to Th17 cells by decreasing pSTAT3 and RORγT transcription factors. Anti-phospho-CD6 Western blot, co-immunoprecipitation of ZAP70/SLP-76 with CD6, intracellular transcription factor staining, cytokine ELISA, in vivo EAE with mouse anti-mouse CD6D1 antibody PloS one Medium 28672038
1997 CD6 gene encodes at least five different isoforms arising from variable splicing of exons encoding the cytoplasmic domain. Each of the three extracellular SRCR domains is encoded by a separate exon. CD6 maps to chromosome 11q13, in close proximity to CD5 and within 600 kb of CD20. Genomic library screening, exon mapping, FISH chromosomal localization, RT-PCR of mRNA transcripts Journal of immunology High 9013954
1990 CD6 is expressed in normal human brain cells (not T cells), as demonstrated by immunohistochemistry with multiple anti-CD6 mAbs and Northern blot analysis detecting a 3.1 kb CD6-specific mRNA in brain regions especially basal ganglia and cortex cerebellum. Immunohistochemistry, Northern blot with cRNA probe, double-staining with hematopoietic cell markers and TCR chain probes Journal of neuroimmunology Medium 2211985
1994 PKC activation by phorbol ester increases CD6 surface expression by increasing CD6 mRNA transcription (~2-3 fold increase in transcription rate shown by nuclear run-on), not by mRNA stabilization. CD2 ligation on thymocytes (but not mature T cells) also upregulates CD6, suggesting developmental regulation of CD6 expression. Nuclear run-on transcription assay, Northern blot, Western blot, actinomycin D chase experiments, PKC inhibitor experiments, anti-CD2 stimulation Journal of immunology High 8207228

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 641 19525953
1995 Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand. The Journal of experimental medicine 326 7760007
2005 Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells. Blood 179 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 155 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 125 9357143
2004 Frontline: Optimal T cell activation requires the engagement of CD6 and CD166. European journal of immunology 123 15048703
2004 Relevance of CD6-mediated interactions in T cell activation and proliferation. Journal of immunology (Baltimore, Md. : 1950) 121 15294938
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
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 103 17601777
2022 The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. The Journal of clinical investigation 89 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 81 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
2016 CD6 modulates thymocyte selection and peripheral T cell homeostasis. The Journal of experimental medicine 76 27377588
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
2011 CD6 attenuates early and late signaling events, setting thresholds for T-cell activation. European journal of immunology 71 21956609
2011 Antioxidative potential of folate producing probiotic Lactobacillus helveticus CD6. Journal of food science and technology 71 24425884
2011 The CD6 multiple sclerosis susceptibility allele is associated with alterations in CD4+ T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 69 21849685
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) 63 26146185
2002 The accessory molecules CD5 and CD6 associate on the membrane of lymphoid T cells. The Journal of biological chemistry 61 12473675
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
2010 The CD6 scavenger receptor is differentially expressed on a CD56 natural killer cell subpopulation and contributes to natural killer-derived cytokine and chemokine secretion. Journal of innate immunity 58 21178331
2007 Extracellular isoforms of CD6 generated by alternative splicing regulate targeting of CD6 to the immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 54 17371992
2002 CD6: expression during development, apoptosis and selection of human and mouse thymocytes. International immunology 54 12039910
1996 Factors that influence activated CD8+ T-cell apoptosis in patients with acute herpesvirus infections: loss of costimulatory molecules CD28, CD5 and CD6 but relative maintenance of Bax and Bcl-X expression. Immunology 53 8881750
2021 The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation. The Journal of experimental medicine 52 33125054
2018 CD6, a Rheostat-Type Signalosome That Tunes T Cell Activation. Frontiers in immunology 50 30619347
2006 Mitogen-activated protein kinase pathway activation by the CD6 lymphocyte surface receptor. Journal of immunology (Baltimore, Md. : 1950) 49 16818773
1996 Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes. Immunology 49 8881754
2005 The lymphocyte receptor CD6 interacts with syntenin-1, a scaffolding protein containing PDZ domains. Journal of immunology (Baltimore, Md. : 1950) 48 16034076
1997 Structure and chromosomal location of the human CD6 gene: detection of five human CD6 isoforms. Journal of immunology (Baltimore, Md. : 1950) 48 9013954
2010 Aberrant expression of CD6 on B-cell subsets from patients with Sjögren's syndrome. Journal of autoimmunity 47 20810246
2016 Tuning T Cell Activation: The Function of CD6 At the Immunological Synapse and in T Cell Responses. Current drug targets 45 26028048
1994 The anti-CD6 mAb, IOR-T1, defined a new epitope on the human CD6 molecule that induces greater responsiveness in T cell receptor/CD3-mediated T cell proliferation. Cellular immunology 45 7509726
1994 Characterization of a CD6 ligand(s) expressed on human- and murine-derived cell lines and murine lymphoid tissues. Cellular immunology 45 7923388
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1989 Structural characterization of CD6: properties of two distinct epitopes involved in T cell activation. Molecular immunology 43 2481822
2017 T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab. PloS one 42 28672038
2014 Dynamic coupling of ALCAM to the actin cortex strengthens cell adhesion to CD6. Journal of cell science 42 24496453
2018 Clinical and experimental evidence for targeting CD6 in immune-based disorders. Autoimmunity reviews 40 29526637
1990 Expression of the CD6 T lymphocyte differentiation antigen in normal human brain. Journal of neuroimmunology 38 2211985
2013 CD6 as a therapeutic target in autoimmune diseases: successes and challenges. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 37 23568178
2012 A clinical exploratory study with itolizumab, an anti-CD6 monoclonal antibody, in patients with rheumatoid arthritis. Results in immunology 37 24371585
2001 CD6+ donor marrow T-cell depletion as the sole form of graft-versus-host disease prophylaxis in patients undergoing allogeneic bone marrow transplant from unrelated donors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 11181681
1997 Identification of residues in CD6 which are critical for ligand binding. Biochemistry 37 9054570
1991 Biosynthesis and post-translational modification of CD6, a T cell signal-transducing molecule. The Journal of biological chemistry 37 2016320
2014 Human treg cells are characterized by low/negative CD6 expression. Cytometry. Part A : the journal of the International Society for Analytical Cytology 35 25088497
2016 Therapeutic Targeting of CD6 in Autoimmune Diseases: A Review of Cuban Clinical Studies with the Antibodies IOR-T1 and Itolizumab. Current drug targets 33 26844560
2008 Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb. The Journal of allergy and clinical immunology 33 19084111
2004 Expression and characterization of a novel CD6 ligand in cells derived from joint and epithelial tissues. Journal of immunology (Baltimore, Md. : 1950) 33 15528349
1998 CD6+ T cell-depleted allogeneic bone marrow transplantation for non-Hodgkin's lymphoma. Bone marrow transplantation 33 9674848
1995 Human CD6 possesses a large, alternatively spliced cytoplasmic domain. European journal of immunology 32 7589069
1990 Phosphorylation-dephosphorylation of the CD6 glycoprotein renders two isoforms of 130 and 105 kilodaltons. Effect of serum and protein kinase C activators. Journal of immunology (Baltimore, Md. : 1950) 32 2384666
2014 ALCAM and CD6--multiple sclerosis risk factors. Journal of neuroimmunology 31 25216742
2010 Validation of the CD6 and TNFRSF1A loci as risk factors for multiple sclerosis in Spain. Journal of neuroimmunology 31 20430450
2018 Targeting CD6 for the treatment of experimental autoimmune uveitis. Journal of autoimmunity 30 29472120
2014 T cell activation regulates CD6 alternative splicing by transcription dynamics and SRSF1. Journal of immunology (Baltimore, Md. : 1950) 30 24890719
2014 Modulation of CD6 function through interaction with Galectin-1 and -3. FEBS letters 30 24945728
2008 Towards the definition of a chimpanzee and human conserved CD6 domain 1 epitope recognized by T1 monoclonal antibody. Hybridoma (2005) 30 18707547
2017 Genetic and experimental evidence for the involvement of the CD6 lymphocyte receptor in psoriasis. Cellular & molecular immunology 29 29225340
2015 Itolizumab - a humanized anti-CD6 monoclonal antibody with a better side effects profile for the treatment of psoriasis. Clinical, cosmetic and investigational dermatology 29 25945063
2011 Rationale for Targeting CD6 as a Treatment for Autoimmune Diseases. Arthritis 29 22076177
2013 Associations of CD6, TNFRSF1A and IRF8 polymorphisms with risk of inflammatory demyelinating diseases. Neuropathology and applied neurobiology 28 22994200
2014 Immunological and histological evaluation of clinical samples from psoriasis patients treated with anti-CD6 itolizumab. mAbs 27 24594862
2003 OX52 is the rat homologue of CD6: evidence for an effector function in the regulation of CD5 phosphorylation. Journal of leukocyte biology 27 12525577
1996 Characterization of mouse CD6 with novel monoclonal antibodies which enhance the allogeneic mixed leukocyte reaction. European journal of immunology 27 8625962
1996 Expression of an avian CD6 candidate is restricted to alpha beta T cells, splenic CD8+ gamma delta T cells and embryonic natural killer cells. European journal of immunology 27 8765015
2020 Attenuation of Murine Collagen-Induced Arthritis by Targeting CD6. Arthritis & rheumatology (Hoboken, N.J.) 26 32307907
2020 Soluble CD5 and CD6: Lymphocytic Class I Scavenger Receptors as Immunotherapeutic Agents. Cells 26 33287301
1994 Isolation and characterization of CD6- T cells from peripheral blood. Journal of immunology (Baltimore, Md. : 1950) 26 7904289
2020 Itolizumab, an anti-CD6 monoclonal antibody, as a potential treatment for COVID-19 complications. Expert opinion on biological therapy 25 32700604
2017 T Cell Costimulation by CD6 Is Dependent on Bivalent Binding of a GADS/SLP-76 Complex. Molecular and cellular biology 25 28289074
2016 CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal. The Journal of biological chemistry 25 27909060
1997 Analysis of the tyrosine phosphorylation and calcium fluxing of human CD6 isoforms with different cytoplasmatic domains. European journal of immunology 25 9394826
2000 Evidence for the expression of a second CD6 ligand by synovial fibroblasts. Arthritis and rheumatism 24 10693872
1995 Production of active anti-CD6 mouse/human chimeric antibodies in the milk of transgenic mice. Immunotechnology : an international journal of immunological engineering 24 9373339
1994 Analyses of monoclonal antibodies reactive with porcine CD6. Veterinary immunology and immunopathology 24 7531907
2002 Risk factors for cytomegalovirus reactivation after CD6+ T-cell-depleted allogeneic bone marrow transplantation. Transplantation 23 12134098
1997 CD6 dependent interactions of T cells and keratinocytes: functional evidence for a second CD6 ligand on gamma-interferon activated keratinocytes. Immunology letters 22 9436462
1994 Transcriptional regulation of CD6 expression on human T lymphocytes by phorbol ester. Journal of immunology (Baltimore, Md. : 1950) 22 8207228
2017 Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses. Frontiers in immunology 21 28713387
2013 Fine mapping and functional analysis of the multiple sclerosis risk gene CD6. PloS one 21 23638056
2016 The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations. Current drug targets 20 26844569
2013 Rationale for treating primary Sjögren's syndrome patients with an anti-CD6 monoclonal antibody (Itolizumab). Immunologic research 20 23576060
2012 CD6 and syntaxin binding protein 6 variants and response to tumor necrosis factor alpha inhibitors in Danish patients with rheumatoid arthritis. PloS one 20 22685579
1996 Recognition of diverse proteins by members of the immunoglobulin superfamily: delineation of the receptor binding site in the human CD6 ligand ALCAM. Biochemistry 20 8823162
1995 Cloning and characterization of murine CD6. Molecular immunology 20 7870060

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