Affinage

CRTAM

Cytotoxic and regulatory T-cell molecule · UniProt O95727

Length
393 aa
Mass
44.6 kDa
Annotated
2026-06-09
28 papers in source corpus 17 papers cited in narrative 17 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

CRTAM is an immunoglobulin-superfamily transmembrane receptor expressed on activated NK cells, CD8+ T cells, NKT cells, and a subset of CD4+ T cells that orchestrates late-phase lymphocyte activation, polarity, and tissue retention through engagement of its ligand Necl-2/CADM1 (PMID:15811952, PMID:16091383, PMID:18329370). CRTAM is displayed as a cell-surface dimer and binds Necl-2 heterotypically with high affinity (Kd ~2 nM), driving tight cell-cell adhesion that can be competed by soluble CRTAM-Ig (PMID:16091383, PMID:32300914, PMID:39263316); structural and domain analyses show that Necl-2 occupies the CRTAM homodimer interface and that the IgC constant domain mediates the homodimerization required for high-affinity IgV-dependent ligand recognition, so ligand binding and self-dimerization are mutually exclusive (PMID:23871486, PMID:32300914, PMID:39263316). Functionally, Necl-2 engagement promotes NK cytotoxicity and CD8+ T cell IFN-gamma secretion and tumor rejection (PMID:15811952), and recruits a Scrib-anchored polarity complex to establish a late (>6 h) phase of T cell polarity that selectively enhances IFN-gamma and IL-22 output (PMID:18329370). CRTAM marks and instructs CD4+ cytotoxic T lymphocyte differentiation, with its intracellular signaling inducing Eomes, granzyme B, and perforin (PMID:26694968). Through CRTAM-CADM1 contacts with dendritic cells, CRTAM mediates antigen-independent retention of activated CD8+ T cells in draining lymph nodes and residency of CD4+CD8+ T cells in the intestinal epithelium, shaping protective and autoimmune responses in vivo (PMID:19752223, PMID:24687959). CRTAM transcription is induced via a JNK-AP-1 element in activated T cells and repressed by ZEB1 (PMID:19695707, PMID:25910959). Recent genetic work establishes CRTAM as a T cell checkpoint that directs CRTAM+ T cells into normal tissues to drive IL-23-centered type 3 immunity, such that its ablation impairs immune-related adverse events without compromising antitumor efficacy (PMID:41786980).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    Established CRTAM as a novel IgSF gene with expression restricted to class I-MHC-restricted T cell subsets, framing it as part of a shared activation program of these lineages.

    Evidence cDNA library subtraction and expression profiling across mouse T cell subsets

    PMID:10811014

    Open questions at the time
    • No ligand or molecular function identified
    • Expression pattern only, no functional assay
  2. 2005 High

    Identified Necl-2/CADM1 as the CRTAM ligand and defined CRTAM as a surface-dimeric adhesion receptor whose heterotypic engagement drives NK/CD8 effector function and target adhesion.

    Evidence Expression cloning, CRTAM-Ig binding/blocking, cytotoxicity and IFN-gamma assays, in vivo tumor rejection

    PMID:15811952 PMID:16091383

    Open questions at the time
    • Intracellular signaling mechanism downstream of CRTAM unresolved
    • Structural basis of dimerization vs ligand binding not yet defined
  3. 2008 High

    Showed CRTAM couples ligand engagement to a Scrib-anchored polarity complex producing a late phase of T cell polarity, linking the receptor to cytokine output (IFN-gamma, IL-22).

    Evidence Immunological synapse imaging, signaling-complex analysis, and cytokine assays in CRTAM+ vs CRTAM- CD4+ T cells

    PMID:18329370

    Open questions at the time
    • Direct CRTAM-Scrib biochemical interaction not detailed
    • Signaling intermediates between CRTAM cytoplasmic tail and polarity machinery unknown
  4. 2009 High

    Demonstrated in vivo that CRTAM-Necl-2 contacts with dendritic cells retain activated CD8+ T cells in lymph nodes and that an AP-1 element drives CRTAM transcription, connecting activation signaling to receptor expression and tissue positioning.

    Evidence CRTAM-/- mice with viral and autoimmune diabetes models plus LN retention assays; luciferase/EMSA/JNK-inhibitor promoter analysis

    PMID:19695707 PMID:19752223

    Open questions at the time
    • Mechanism of antigen-independent late retention incompletely defined
    • How JNK-AP-1 integrates with later repressors not addressed
  5. 2010 Medium

    Extended CRTAM beyond lymphocytes by showing epithelial CRTAM at lateral membranes participates in homotypic and heterotypic adhesion controlling barrier integrity.

    Evidence Immunofluorescence localization, TEER measurement, soluble CRTAM and antibody blocking in epithelial cultures

    PMID:20556794

    Open questions at the time
    • No genetic knockout in epithelium
    • Physiological relevance of epithelial CRTAM in vivo unclear
  6. 2013 High

    Resolved the structural logic of the receptor: Necl-2 binds the CRTAM homodimer interface so ligand engagement and self-dimerization are mutually exclusive, and defined CRTAM-triggered autophagic death of gammadelta T cells via membrane capture.

    Evidence X-ray crystallography of Necl-2/CRTAM with mutagenesis; co-culture with autophagy/apoptosis/necroptosis markers and inhibitors

    PMID:23530148 PMID:23871486

    Open questions at the time
    • Functional consequence of dimer-to-monomer switching during signaling not established
    • Mechanism linking CRTAM engagement to autophagy machinery unknown
  7. 2014 High

    Established CRTAM-CADM1 as the receptor-ligand pair required for residency of CD4+CD8+ intestinal intraepithelial T cells and mucosal Th17 responses, using both receptor and ligand knockouts.

    Evidence Crtam-/- and Cadm1-/- phenotyping, intestinal T cell flow cytometry, T. gondii infection model

    PMID:24687959

    Open questions at the time
    • Signaling driving residency vs migration not dissected
    • Whether CRTAM acts on the lymphocyte or via ligand-bearing DC dominates is partially open
  8. 2015 High

    Defined CRTAM as a marker and driver of CD4+ cytotoxic T lymphocyte differentiation through intracellular signaling that induces Eomes/granzyme B/perforin, and identified ZEB1 (STAT3-controlled) as a transcriptional repressor of CRTAM.

    Evidence Ectopic CRTAM expression with gene-expression profiling and cytotoxicity assays; ZEB1 overexpression with E-box promoter mutagenesis

    PMID:25910959 PMID:26694968

    Open questions at the time
    • Identity of CRTAM cytoplasmic signaling adaptors driving Eomes still unknown
    • Direct vs indirect role of STAT3 on ZEB1 not fully causally tested
  9. 2019 Low

    Linked CRTAM/Necl-2 to NK cell dysfunction by associating the interaction with an exhaustion-like, suppressive NK phenotype in leukemic bone marrow.

    Evidence Flow cytometry of BM NK subsets and in vitro IL-10/TGF-beta cytokine assays

    PMID:30791148

    Open questions at the time
    • No genetic proof of CRTAM causality in the exhaustion phenotype
    • In vitro association only, not validated in vivo
  10. 2026 High

    Positioned CRTAM as a T cell checkpoint for immune-related adverse events, showing CRTAM+ T cells traffic to normal tissue via CRTAM-CADM1 to drive IL-23 type 3 immunity, separable from antitumor activity.

    Evidence Crtam global and T-cell-specific knockouts in preclinical irAE and tumor models with transcriptome and pharmacovigilance integration

    PMID:41786980

    Open questions at the time
    • Mechanism by which CRTAM-CADM1 biases tissue over tumor infiltration not fully resolved
    • Direct link from CRTAM signaling to IL-23 induction not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intracellular signaling cascade linking CRTAM's cytoplasmic tail to its diverse outputs (polarity, Eomes induction, retention, IL-23) remains undefined.
  • No characterized proximal signaling adaptors of the CRTAM tail
  • Unclear how a single receptor produces adhesion, polarity, differentiation, and cytokine programs in different contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 5
Partners
CADM1SCRIBZEB1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CRTAM was identified as a new immunoglobulin superfamily member expressed on activated mouse alphabetaTCR+ CD4-CD8- NKT cells, with restricted expression in class I-MHC-restricted T cells, suggesting a gene expression program common to this T cell subset. cDNA library subtraction, expression pattern analysis Journal of leukocyte biology Medium 10811014
2005 CRTAM functions as a receptor on NK cells and CD8+ T cells that binds tumor suppressor Necl-2 (TSLC1/CADM1); CRTAM-Necl-2 interaction promotes NK cell cytotoxicity and IFN-gamma secretion by CD8+ T cells in vitro, and NK cell-mediated tumor rejection in vivo. Receptor-ligand binding assays, in vitro cytotoxicity assays, IFN-gamma secretion assays, in vivo tumor rejection model Blood High 15811952
2005 CRTAM is expressed as a dimer on the cell surface of activated NK cells and CD8+ T cells; CRTAM binds Necl-2 heterotypically (not homotypically), and this interaction mediates tight cell-cell adhesion between CRTAM+ lymphocytes and Necl-2+ target cells, which can be blocked by soluble CRTAM-Ig fusion protein. Expression cloning, CRTAM-Ig fusion protein binding assays, cell adhesion/aggregation assays, inhibition with soluble CRTAM-Ig International immunology High 16091383
2008 CRTAM coordinates a signaling complex anchored by the Scrib polarity protein to establish a late phase (>6 hours post-activation) of T cell polarity on a subset of CD4+ T cells; this late polarity selectively enables CD4+CRTAM+ T cells to produce more IFN-gamma and IL-22. Immunological synapse imaging, signaling complex analysis, cytokine production assays in CRTAM+ vs CRTAM- CD4+ T cells Cell High 18329370
2009 CRTAM mediates retention of activated CD8+ T cells within the draining lymph node by binding Necl-2 on CD8+ dendritic cells in the T cell area in an antigen-independent fashion at late-stage activation; CRTAM-/- mice show reduced CD8+ T cell numbers in draining lymph nodes, impaired protective immunity against viral infection, and impaired autoimmune diabetes induction. CRTAM-/- mouse generation, in vivo viral infection model, autoimmune diabetes model, lymph node retention assays, DC binding assays Journal of immunology High 19752223
2009 CRTAM gene expression in human CD8+ T cells is driven by an AP-1 binding site located 1.4 kb upstream of the ATG codon, activated via the JNK-AP-1 signaling pathway; mutation of the AP-1 site abolishes CRTAM promoter activity in activated but not resting T cells. Luciferase reporter assays, EMSA, supershift assays, JNK inhibitor (SP600125) treatment, site-directed mutagenesis of AP-1 element Molecular immunology High 19695707
2009 CRTAM is constitutively expressed in adult thymocytes throughout all stages of thymocyte development (restricted to CD8 and DN subpopulations from E13.5 to adult); blocking CRTAM-CADM1 interaction impairs thymus growth and thymocyte maturation. Flow cytometry of thymic subsets, developmental time-course analysis, CADM1 blocking experiments in thymus Developmental and comparative immunology Medium 19799932
2010 CRTAM is expressed in epithelial cells at the lateral membrane and participates in both homotypic and heterotypic cell adhesion; treatment with soluble CRTAM enhances cell-cell dissociation and lowers transepithelial electrical resistance; anti-CRTAM antibody decreases cell aggregate formation and promotes cell detachment. Immunofluorescence localization, transepithelial electrical resistance measurement, soluble CRTAM treatment, anti-CRTAM antibody blocking, co-culture binding assays Journal of cellular biochemistry Medium 20556794
2013 Crystal structure of the Necl-2/CRTAM complex shows that Necl-2 occupies the CRTAM homodimer interface, making CRTAM homodimerization impossible; mutational analysis identified key 'lock-and-key' amino acids responsible for binding; Necl-2 binding to CRTAM competes with CRTAM dimerization. X-ray crystallography of Necl-2/CRTAM complex, site-directed mutagenesis, functional binding assays Structure High 23871486
2013 CRTAM engagement by Necl-2 on tumor cells triggers cell death of activated Vgamma9Vdelta2 T cells via an autophagic process (not apoptosis or necroptosis); CRTAM is acquired at the tumor cell surface through membrane capture from Vgamma9Vdelta2 T cells upon contact. Co-culture experiments, autophagy/apoptosis/necroptosis marker analysis, specific pathway inhibitors, flow cytometry for CRTAM membrane transfer Journal of immunology Medium 23530148
2014 CRTAM-CADM1 (Necl-2) interactions are required for residency of CD4+CD8+ T cells in the intestinal epithelium; CRTAM is expressed on activated intraepithelial T cells while CADM1 is expressed on gut CD103+ DCs; Crtam-/- and Cadm1-/- mice both lose intestinal CD4+CD8+ T cells; during T. gondii infection, loss of CRTAM results in markedly reduced Th17 cells in the intestinal mucosa. Crtam-/- and Cadm1-/- mouse phenotyping, flow cytometry of intestinal T cell populations, T. gondii infection model, expression analysis of ligand/receptor on specific cell types The Journal of experimental medicine High 24687959
2015 CRTAM expression marks a precursor population for CD4+ cytotoxic T lymphocytes (CD4+CTL); ectopic expression of CRTAM in T cells induces IFN-gamma production, CTL-related gene expression (Eomes, Granzyme B, perforin), and cytotoxic activity; CRTAM-mediated intracellular signaling is required for CD4+CTL induction. Ectopic CRTAM expression, gene expression profiling, IFN-gamma and cytokine assays, cytotoxicity assays, signaling mutant analysis The Journal of experimental medicine High 26694968
2015 ZEB1 (zinc finger E-box-binding protein) functions as a transcriptional repressor of CRTAM in T cells; ZEB1 overexpression represses CRTAM promoter activity and endogenous CRTAM levels; ZEB1-mediated repression is abolished when E-box-like elements in the CRTAM promoter are mutated; STAT3 controls ZEB1 expression downstream of IL-6 and IL-27 signaling. Luciferase reporter assays, site-directed mutagenesis of E-box elements, ZEB1 overexpression, endogenous CRTAM protein measurement Molecular immunology Medium 25910959
2019 In leukemic bone marrow (ALL), CRTAM/Necl-2 interaction drives NK cells into an exhaustion-like phenotype with suppressive functions (IL-10 and TGF-beta production in vitro); preactivated CD56high NK cells expressing CRTAM are enriched in leukemic bone marrow. Flow cytometry of bone marrow NK populations, in vitro cytokine production assays (IL-10, TGF-beta), phenotypic characterization of exhaustion markers Journal of leukocyte biology Low 30791148
2020 The IgC constant domain of CRTAM forms a homodimer in solution via hydrophobic interactions and is essential for high-affinity binding to Necl-2; the IgV domain mediates ligand recognition but requires the IgC domain for high-affinity interaction (Kd = 2.16 nM by SPR); recombinant CRTAM recognizes Necl-2 in a cell-free system only when the stalk region is included. Recombinant protein purification, surface plasmon resonance (SPR), cell-free binding assay, domain deletion analysis The protein journal / Biochemistry and biophysics reports High 32300914 39263316
2026 CRTAM acts as a T cell checkpoint for immune-related adverse events (irAEs) during immune checkpoint blockade; CRTAM+ T cells preferentially infiltrate normal tissues over tumors via CRTAM-CADM1 interaction and promote IL-23-centered type 3 immunity; Crtam knockout or T cell lineage-specific Crtam ablation impairs irAE induction without affecting antitumor efficacy. Crtam knockout mice, T cell lineage-specific Crtam ablation, preclinical irAE models, tumor-bearing irAE models, transcriptome and pharmacovigilance data integration Nature cancer High 41786980
2024 IL-6 and IL-27 negatively regulate CRTAM expression on activated naïve CD4+ T cells; this regulation operates through STAT3-mediated control of the CRTAM transcriptional repressor ZEB1. Ex vivo T cell activation with IL-6/IL-27, STAT3 pathway analysis, ZEB1 expression measurement, flow cytometry bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. The Journal of experimental medicine 174 26694968
2005 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM. Blood 158 15811952
2008 Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 104 18329370
2000 A molecular analysis of NKT cells: identification of a class-I restricted T cell-associated molecule (CRTAM). Journal of leukocyte biology 68 10811014
2005 Heterotypic interaction of CRTAM with Necl2 induces cell adhesion on activated NK cells and CD8+ T cells. International immunology 63 16091383
2009 CRTAM confers late-stage activation of CD8+ T cells to regulate retention within lymph node. Journal of immunology (Baltimore, Md. : 1950) 56 19752223
2014 CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection. The Journal of experimental medicine 50 24687959
2011 Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM. Cellular & molecular immunology 42 21572449
2011 Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations. The Journal of allergy and clinical immunology 37 22051697
2019 CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow. Journal of leukocyte biology 17 30791148
2010 CRTAM: A molecule involved in epithelial cell adhesion. Journal of cellular biochemistry 17 20556794
2013 CRTAM receptor engagement by Necl-2 on tumor cells triggers cell death of activated Vγ9Vδ2 T cells. Journal of immunology (Baltimore, Md. : 1950) 13 23530148
2013 Competition of cell adhesion and immune recognition: insights into the interaction between CRTAM and nectin-like 2. Structure (London, England : 1993) 13 23871486
2009 Ethanol-responsive genes (Crtam, Zbtb16, and Mobp) located in the alcohol-QTL region of chromosome 9 are associated with alcohol preference in mice. Alcoholism, clinical and experimental research 13 19413645
2009 Characterization of CRTAM gene promoter: AP-1 transcription factor control its expression in human T CD8 lymphocytes. Molecular immunology 13 19695707
2019 CRTAM Protects Against Intestinal Dysbiosis During Pathogenic Parasitic Infection by Enabling Th17 Maturation. Frontiers in immunology 12 31312200
2009 Role of CRTAM during mouse early T lymphocytes development. Developmental and comparative immunology 12 19799932
2019 CRTAM Shapes the Gut Microbiota and Enhances the Severity of Infection. Journal of immunology (Baltimore, Md. : 1950) 11 31142601
2024 CRTAM promotes antitumor immune response in triple negative breast cancer by enhancing CD8+ T cell infiltration. International immunopharmacology 9 38354509
2015 CRTAM is negatively regulated by ZEB1 in T cells. Molecular immunology 8 25910959
2014 [Nectins and nectin-like receptors DNAM-1 and CRTAM: new ways for tumor escape]. Medecine sciences : M/S 8 24939541
2023 Molecular characterization of the cytotoxic and regulatory T cell coreceptor (CRTAM), and its ligand CADM1, in the European seabass and gilthead seabream. Fish & shellfish immunology 4 36720375
2020 Prokaryotic Expression of the Immunoglobulin's Domains of CRTAM to Characterize a Monoclonal Antibody. The protein journal 3 32300914
2013 Chicken CRTAM binds nectin-like 2 ligand and is upregulated on CD8+ αβ and γδ T lymphocytes with different kinetics. PloS one 3 24339981
2024 Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn's Disease. Pharmaceutics 2 38931955
2024 The constant domain of CRTAM is essential for high-affinity interaction with Nectin-like 2. Biochemistry and biophysics reports 1 39263316
2026 CRTAM inhibition mitigates toxicity of immune checkpoint inhibitors without antitumor efficacy trade-off. Nature cancer 0 41786980
2020 Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies. International journal of molecular sciences 0 33233764

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