{"gene":"SLAMF6","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2001,"finding":"NTB-A (SLAMF6) undergoes tyrosine phosphorylation upon stimulation and associates with the SH2 domain-containing adaptor SH2D1A (SAP) as well as SH2 domain-containing phosphatases (SHPs). In XLP NK cells lacking SAP, NTB-A mediates inhibitory rather than activating signals, demonstrating SAP-dependent switch between activating and inhibitory signaling.","method":"Molecular cloning, tyrosine phosphorylation assays, co-immunoprecipitation with SAP and SHPs, functional NK cytotoxicity assays in XLP patient cells, antibody masking experiments","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical co-IP, phosphorylation assay, functional assays in patient cells), foundational mechanistic paper replicated by subsequent work","pmids":["11489943"],"is_preprint":false},{"year":2004,"finding":"SLAMF6 (NTB-A/NTBA) is its own ligand, engaging in homophilic (self-self) interaction. A chimeric NTBA-Fc fusion protein specifically binds NTBA-expressing cells but not cells transfected with other CD2 family members, confirmed by ELISA, surface plasmon resonance (plasmon resonance analysis), and NTBA-Fc-mediated downregulation of surface NTBA expression. Homophilic engagement induces NK cell IFN-γ and TNF-α production and increases susceptibility of NTBA-expressing targets to NK-mediated killing.","method":"Chimeric Fc-fusion protein binding assay, ELISA, plasmon resonance, surface expression downregulation assay, NK cytotoxicity assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted homophilic binding in vitro using multiple orthogonal methods (SPR, ELISA, downregulation), independently confirmed by Flaig et al. 2004","pmids":["15162436"],"is_preprint":false},{"year":2004,"finding":"NTB-A (SLAMF6) activates NK cells via homophilic interaction; trimeric recombinant NTB-A proteins demonstrated that NTB-A is its own ligand and that this homophilic engagement enhances NK cell cytotoxicity, proliferation, and IFN-γ secretion.","method":"Trimeric recombinant protein binding assay, NK cytotoxicity assay, proliferation assay, cytokine secretion assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution with recombinant proteins, replicates findings of Falco et al. 2004 by independent lab","pmids":["15153464"],"is_preprint":false},{"year":2004,"finding":"NTB-A (SLAMF6) cross-linking in T cells induces phosphorylation of NTB-A and association with SAP, promotes T cell proliferation, IFN-γ secretion, and Th1 differentiation (not IL-4/Th2). In vivo blocking with soluble NTB-A-Fc inhibits B cell isotype switching to IgG2a/IgG3, and delays onset of experimental autoimmune encephalomyelitis in transgenic mice.","method":"Antibody cross-linking, phosphorylation assay, co-immunoprecipitation with SAP, cytokine ELISA, T cell differentiation assays, in vivo EAE model with NTB-A-Fc treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab (biochemical + in vivo), no independent replication cited","pmids":["14988414"],"is_preprint":false},{"year":2005,"finding":"Ly108 (SLAMF6) controls T cell cytokine responses and neutrophil bactericidal activity. Mice with targeted disruption of Ly108 exons 2 and 3 show reduced IL-4 production by CD4+ T cells and defective neutrophil bactericidal activity due to severely reduced production of reactive oxygen species following phagocytosis.","method":"Targeted gene disruption (knockout mice), in vitro cytokine assays, in vivo Leishmania infection model, Salmonella infection model, ROS production assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with specific phenotypic readouts (ROS, cytokines), single lab","pmids":["15879084"],"is_preprint":false},{"year":2006,"finding":"The 3.0 Å crystal structure of the complete NTB-A (SLAMF6) ectodomain reveals a rod-like monomer that self-associates to form a highly kinked dimer spanning ~100 Å end-to-end. The NTB-A homophilic dimer shows overall structural similarity to CD2-CD58 heterophilic dimer but differs in detailed interface organization. The structure suggests a mechanism for binding specificity within the SLAM family and imposes constraints on colocalization with other signaling molecules at the immunological synapse.","method":"X-ray crystallography at 3.0 Å resolution, analytical ultracentrifugation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional interpretation, rigorous single study with structural validation","pmids":["17045824"],"is_preprint":false},{"year":2006,"finding":"NTB-A (SLAMF6) is constitutively tyrosine phosphorylated in unstimulated human NK cells by Src family kinases, likely due to homophilic interaction among neighboring NK cells. The cytoplasmic tail contains three tyrosines in immunoreceptor tyrosine-based switch motifs; the second tyrosine is sufficient and essential for NTB-A-mediated cytotoxicity. EAT-2 (not SAP) is recruited to this second tyrosine for cytotoxicity, while SAP is required for IFN-γ production, demonstrating that cytokine production and cytotoxicity are differentially dependent on SAP versus EAT-2.","method":"NTB-A tyrosine mutant expression in NTB-A-negative NK cell line, SAP knockdown by siRNA, functional cytotoxicity and cytokine assays, co-immunoprecipitation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis of tyrosine residues, genetic knockdown, multiple functional readouts, single rigorous study with multiple orthogonal methods","pmids":["16920955"],"is_preprint":false},{"year":2006,"finding":"The Ly108.2 allele (normal), but not the lupus-associated Ly108.1 allele, sensitizes immature B cells to deletion and RAG reexpression, establishing Ly108 (SLAMF6) as a regulator of B cell tolerance checkpoints.","method":"Allele-specific expression analysis, B cell tolerance assays (anergy, deletion, receptor revision) in congenic mouse strains","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific functional comparison in congenic strains, single lab, specific B cell tolerance readouts","pmids":["16778059"],"is_preprint":false},{"year":2007,"finding":"Homotypic interactions mediated by Slamf1 and Slamf6 (Ly108) generate co-stimulatory 'second signals' downstream of TCR engagement during T-T (thymocyte-thymocyte) interactions; these signals recruit SAP and Src kinase Fyn and are essential for NKT cell lineage expansion and differentiation. Ligand recognition on thymocytes (which express Slamf6) but not stromal epithelial cells (which do not) determines the availability of this co-signaling pathway.","method":"Genetic mouse models (Slamf6 knockout, SAP knockout, Fyn knockout), thymocyte co-culture assays, NKT cell developmental analysis by flow cytometry","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis using multiple genetic knockouts, replicated across several receptor/adaptor/kinase knockouts, specific developmental readouts","pmids":["18031695"],"is_preprint":false},{"year":2008,"finding":"Ly108 (SLAMF6) mediates tyrosine phosphorylation signals in T cells implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on SAP co-expression and extracellular domain engagement. SAP recruits FynT to mediate this phosphorylation. The lupus-associated isoform Ly108-1 more potently triggers tyrosine phosphorylation than the non-lupus Ly108-2 isoform, partly due to a unique intracytoplasmic tyrosine-based motif in Ly108-1.","method":"Tyrosine phosphorylation assays, co-immunoprecipitation, analysis of SAP-FynT pathway mutant T cells, isoform comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution with multiple genetic controls (SAP-null, FynT-null mice), isoform mutagenesis comparison, single rigorous lab study","pmids":["18482989"],"is_preprint":false},{"year":2010,"finding":"HIV-1 Vpu downmodulates NTB-A (SLAMF6) on infected CD4+ T cells, associating with NTB-A through its transmembrane region without promoting NTB-A degradation. This prevents homophilic NTB-A engagement between NK cells and infected targets, thereby reducing NK cell degranulation. Cells infected with Vpu mutant virus elicited at least 50% more NK cells to degranulate than wild-type virus.","method":"Co-immunoprecipitation of Vpu with NTB-A, flow cytometry of surface NTB-A, NK degranulation assays, Vpu mutant virus comparison","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct co-IP identifying Vpu-NTB-A interaction via transmembrane domain, functional degranulation assays, mutant virus controls","pmids":["21075351"],"is_preprint":false},{"year":2011,"finding":"SLAMF6 co-engagement with CD3 under Th17-polarizing conditions increases IL-17 production in a SAP-dependent manner. SLAMF3/SLAMF6 co-stimulation is more potent and prolonged than CD28 co-stimulation for IL-17 induction in both naive and memory CD4+ T cells from normal donors, but is defective in SLE T cells.","method":"Antibody co-stimulation assays, intracellular cytokine staining, correlation with disease activity, SAP requirement established by comparison with XLP patients","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-stimulation assays with SAP requirement established via XLP patient cells, single lab, multiple patient cohorts","pmids":["22184727"],"is_preprint":false},{"year":2011,"finding":"The Ly108-H1 isoform of SLAMF6, absent in lupus-prone congenic mice, suppresses T cell-dependent autoimmunity. Introduction of an Ly108-H1-expressing transgene markedly diminishes autoantibody production and T cell-driven pathology in B6.Sle1b mice, identifying this isoform as a disease-suppressing regulatory form.","method":"Transgenic mouse overexpression, autoantibody assays, in vivo lupus model (B6.Sle1b congenic)","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic rescue experiment in congenic disease model, single lab, specific functional readout","pmids":["21422172"],"is_preprint":false},{"year":2012,"finding":"Deletion of Ly108 (Slamf6) in CD4+ T cells reverses the SAP-deficiency phenotype, eliminating the SAP requirement for germinal centers. Ly108 exerts potent negative signaling requiring ITSMs and SHP-1 recruitment, resulting in high SHP-1 at the T cell:B cell synapse, limiting T cell:B cell adhesion. SLAMF6-negative signaling also contributes to NKT cell differentiation defect in SAP-null mice.","method":"Genetic epistasis (Slamf6-/-/Sh2d1a-/- double knockout mice), germinal center analysis, NKT cell developmental assays, ITSM mutagenesis, SHP-1 recruitment assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic epistasis with double KO, ITSM mutagenesis, multiple orthogonal functional readouts, single rigorous study","pmids":["22683125"],"is_preprint":false},{"year":2012,"finding":"Ly108 (SLAMF6) is constitutively tyrosine phosphorylated in murine thymi in a SAP- and Fyn kinase-dependent manner. Phosphorylation is dynamically regulated by cell-cell contact (lost rapidly after thymocyte disaggregation). Distinct isoforms are differentially expressed in lupus-resistant versus lupus-prone mouse strains; the Ly108-H1 isoform does not undergo tyrosine phosphorylation, suggesting it functions as a decoy isoform.","method":"Tyrosine phosphorylation analysis of thymic lysates, disaggregation kinetics, isoform-specific expression analysis, comparison of SAP-null and Fyn-null mice","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical analysis with genetic controls (SAP-null, Fyn-null), isoform-specific phosphorylation, single lab","pmids":["22393150"],"is_preprint":false},{"year":2013,"finding":"Ly108 (SLAMF6) co-stimulation of double-positive thymocytes markedly enhances expression of the transcription factor PLZF (encoded by Zbtb16) compared to TCR stimulation alone. This is mediated through increased Egr-2 expression and enhanced Egr-2 binding to the Zbtb16 promoter; CD28 co-stimulation failed to enhance Egr-2 binding or PLZF levels. Ly108-deficient mice show decreased numbers of PLZF-expressing CD4+ T cells.","method":"Thymocyte co-stimulation assays, ChIP assay (Egr-2 binding to Zbtb16 promoter), flow cytometry, Ly108-deficient mouse analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP assay establishing direct transcription factor recruitment, KO mouse confirmation, multiple orthogonal methods in single rigorous study","pmids":["23355739"],"is_preprint":false},{"year":2013,"finding":"HIV-1 Vpu prevents formation of the mature glycoform of NTB-A (SLAMF6) by retaining NTB-A within the Golgi compartment; only the high-mannose (immature) form is detectable in the presence of Vpu. This mechanism is distinct from Vpu-mediated downregulation of CD4 and tetherin and is highly conserved among HIV-1 and SIV Vpu proteins.","method":"Glycosylation analysis (EndoH/PNGaseF digestion), immunofluorescence/confocal microscopy for Golgi retention, comparison of multiple Vpu variants","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical glycosylation analysis with subcellular localization imaging, single lab, multiple Vpu variants tested","pmids":["23528733"],"is_preprint":false},{"year":2014,"finding":"SAP facilitates recruitment and activation of LCK (but not FYN) at NTB-A (SLAMF6) receptors in activated T cells. Upon TCR restimulation, LCK association with NTB-A increases in a SAP-dependent manner, requiring both ITSMs in the NTB-A cytoplasmic tail. NTB-A-associated LCK phosphorylation and kinase activity are enhanced, amplifying proximal TCR signaling and promoting restimulation-induced cell death (RICD). In XLP T cells (SAP-null), this association and RICD are reduced.","method":"Co-immunoprecipitation of LCK with NTB-A, LCK kinase activity assay, RICD assay, ITSM requirement analysis, SAP siRNA knockdown, XLP patient T cells","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP with kinase activity assay, genetic controls (XLP patient cells, SAP siRNA), ITSM requirement, multiple orthogonal methods","pmids":["24688028"],"is_preprint":false},{"year":2014,"finding":"Ly108 (SLAMF6) dampens T cell adhesion to antigen-presenting B cells and dendritic cells by inhibiting CD3ζ phosphorylation through two mechanisms: (1) constitutive colocalization with CD3 complex within 100-200 nm on quiescent cells reducing CD3ζ phosphorylation independent of ligation; (2) ligation-dependent Ly108-CD3ζ interaction promoted by Ly108 transmembrane domain leading to more efficient CD3ζ dephosphorylation via constitutively associated SHP-1. Replacement of Ly108 TM domain abrogates ligation-dependent inhibition and suppression of T-B adhesion.","method":"FRET/imaging within 100-200 nm, transmembrane domain replacement mutants, CD3ζ phosphorylation assay, T cell-APC adhesion assay, SHP-1 co-immunoprecipitation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mutants with specific phosphorylation readouts, proximity imaging, multiple orthogonal methods in single rigorous study","pmids":["25217164"],"is_preprint":false},{"year":2015,"finding":"SLAMF1, SLAMF5, and SLAMF6 act synergistically as negative regulators of humoral immunity. Adoptive co-transfer experiments showed that [Slamf1+5+6]-/- B cells (more than T cells) drive enhanced antibody responses; anti-SLAMF6 monoclonal antibody severely inhibits Tfh cell and germinal center B cell development, confirming SLAMF6's suppressive role in humoral responses.","method":"Triple knockout mice, T-independent and T-dependent antibody assays, adoptive co-transfer experiments, anti-SLAMF6 mAb treatment","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and antibody-mediated loss-of-function with specific GC/Tfh readouts, single lab, multiple experimental approaches","pmids":["25926831"],"is_preprint":false},{"year":2015,"finding":"SLAMF6 (Slamf6) engages structures on the outer cell membrane of several Gram-negative bacteria (demonstrated by reporter-based binding assay), and Slamf6-mediated interactions of colonic innate immune cells with specific Gram-negative bacteria reduce mucosal protection and enhance inflammation; Slamf6 deficiency in Rag-/- mice reduces inflammatory pathology and bacterial translocation during Citrobacter rodentium infection, while enhancing IL-22 production.","method":"Reporter-based bacterial binding assay, Slamf6-/- Rag-/- mouse infection model, anti-Slamf6 mAb blocking of bacterial interactions, cytokine analysis","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus in vivo KO model with specific immune readouts, single lab","pmids":["25957267"],"is_preprint":false},{"year":2016,"finding":"SLAMF6 on NK cells, together with SAP family adaptors and SHP-1 phosphatase, regulates NK cell education. SLAMF6 expressed on hematopoietic cells enhances NK cell activation by nonhematopoietic target cells (which lack SLAM receptor ligands); SAP adaptors uncouple SLAM receptors from SHP-1, diminishing SLAMF6's effect on NK cell responsiveness toward nonhematopoietic cells.","method":"SLAMF6 knockout mice, SAP adaptor knockout mice, NK cell education assays, hematopoietic chimera experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection with multiple KO models, hematopoietic chimeras, rigorous mechanistic epistasis, high-impact journal","pmids":["26878112"],"is_preprint":false},{"year":2016,"finding":"Transfer of Slamf6-/- CD4+ T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated autoantibodies, Tfh cells, IFN-γ-producing CD4+ cells, and GC B cells. This pathology requires Slamf1 co-expression (Slamf[1+6]-/- cells did not induce increased autoantibodies), placing SLAMF6 as an inhibitory receptor whose absence, in combination with Slamf1, drives autoimmune responses. The Slamf6-H1 isoform expressed in Slamf6-/- T cells did not induce this phenotype.","method":"Adoptive transfer of KO T cells, flow cytometry for Tfh/GC B cells, autoantibody ELISA, double KO epistasis","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with adoptive transfer, specific autoimmune readouts, single lab","pmids":["27368806"],"is_preprint":false},{"year":2017,"finding":"Naive B and T cells interact via homophilic SLAMF6 engagement at their surface, generating cell-type-specific SAP-dependent signals: T cells upregulate migration inhibitory factor (MIF), while B cells upregulate CD74 (MIF receptor), consequently enhancing B cell survival. In XLP patients (SAP-deficient), this interaction is disrupted, reducing CD74 expression and impairing naive B cell maintenance.","method":"Co-culture of naive B and T cells, antibody blocking of SLAMF6, cytokine/receptor expression analysis, XLP patient cells, SAP-null comparison","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-cell interaction assay with blocking antibody and XLP patient validation, identification of MIF-CD74 axis, single lab","pmids":["28904129"],"is_preprint":false},{"year":2012,"finding":"CD3-T cell receptor co-stimulation through SLAMF3 and SLAMF6 enhances recruitment of RORγt to the IL17A promoter in human T lymphocytes, beyond the effect of NFAT1 recruitment that is shared with CD28 co-stimulation. The dominance of SLAMF3/SLAMF6 pathway in IL-17A induction is attributed to increased nuclear abundance and IL17A promoter binding of RORγt.","method":"ChIP assay for NFAT1 and RORγt binding to IL17A promoter, nuclear fractionation, co-stimulation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP assay establishing direct transcription factor recruitment to promoter, single lab","pmids":["22989874"],"is_preprint":false},{"year":2013,"finding":"NK cell cytotoxicity mediated by NTB-A (SLAMF6) is SAP-dependent, but the role of SAP is downstream of receptor phosphorylation and lipid raft recruitment (both of which are unaffected by SAP loss). EAT-2 recruitment to NTB-A is abrogated in the absence of SAP, revealing cooperativity between SAP and EAT-2 adaptors.","method":"SAP knockdown in primary NK cells, raft recruitment analysis, phosphorylation assay, EAT-2 knockdown, cytotoxicity assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with specific signaling dissection, multiple readouts, single lab","pmids":["23346089"],"is_preprint":false},{"year":2016,"finding":"Using CRISPR/Cas9 to generate triple knockout (SLAMF1/SLAMF5/SLAMF6 TKO) mice, combined deletion worsened iNKT cell developmental defects compared to SLAMF6 single knockout, supporting positive signaling roles and potential redundancy among these receptors in iNKT cell development. Germinal center formation was only mildly defective in TKO mice.","method":"CRISPR/Cas9 triple gene knockout, iNKT cell developmental analysis by flow cytometry, germinal center analysis post-immunization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with CRISPR triple KO, specific iNKT developmental readout, single lab","pmids":["27258160"],"is_preprint":false},{"year":2016,"finding":"2B4 and NTB-A (SLAMF6) directly recognize influenza viral hemagglutinin (HA) protein on infected cells, co-stimulating NK cell cytotoxicity. These interactions require sialylation of the receptors. The virus neuraminidase (NA) protein counters these interactions by desialylating the receptors.","method":"Direct binding assays between recombinant receptors and HA, sialylation dependency experiments, NA treatment, NK cytotoxicity assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding assays with recombinant proteins, sialylation manipulation, single lab","pmids":["26919106"],"is_preprint":false},{"year":2019,"finding":"SLAMF6 functions as a co-stimulatory receptor requiring its ectodomain for function (but not for recruitment to the immunological synapse); tyrosine 308 in the cytoplasmic tail is crucial for T cell activation enhancement. SLAMF6 clustering with the TCR (demonstrated by imaging) dramatically increases downstream signaling. SLAMF6 enhances T cell function by increasing T cell adhesiveness through activation of the small GTPase Rap1.","method":"Biochemical and genetic experiments (SLAMF6 domain mutants), flow cytometry, live-cell imaging, Rap1 activation assay, T cell adhesion assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (domain mutants, imaging, GTPase assay), single lab","pmids":["31199820"],"is_preprint":false},{"year":2020,"finding":"SLAMF6 deficiency in CD8+ T cells augments anti-tumor cytolysis and skews toward an effector phenotype with T-bet as the dominant transcription factor. Adoptive transfer of SLAMF6-/- Pmel-1 T cells to melanoma-bearing mice results in lasting tumor regression. SLAMF6 absence increases LAG-3 expression on CD8+ T cells, and combinatorial LAG-3 blockade further improves anti-tumor responses, establishing SLAMF6 as an inhibitory immune checkpoint for CD8+ T cells.","method":"Pmel-1 x SLAMF6-/- mouse generation, adoptive transfer into melanoma models (B16, Eμ-TCL1), flow cytometry for T cell phenotype, transcription factor analysis (T-bet), degranulation assays, combination antibody treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo tumor models, multiple functional readouts, mechanistic transcription factor analysis, single rigorous multi-experiment study","pmids":["32122464"],"is_preprint":false},{"year":2021,"finding":"SLAMF6 has three splice isoforms involving its V-domain in humans. The canonical receptor inhibits T cell activation through SAP recruitment, while the short isoform SLAMF6Δ17-65 has strong agonistic/costimulatory effects. The costimulatory action of SLAMF6Δ17-65 is SHP-1-dependent and leads to a cytotoxic molecular profile mediated by expression of TBX21 and RUNX3. Splice-switching antisense oligonucleotides (ASOs) targeting the SLAMF6 splice junction enhance SLAMF6Δ17-65 expression in TILs and improve their anti-melanoma capacity in mice.","method":"Isoform cloning and expression, T cell activation assays comparing isoforms, SHP-1 inhibitor experiments, transcription factor analysis, ASO design and testing in TILs, in vivo melanoma model","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — isoform-specific functional comparison with mechanistic follow-up (SHP-1 dependence, transcription factors), in vivo confirmation, single rigorous multi-experiment study","pmids":["33762352"],"is_preprint":false},{"year":2022,"finding":"SLAMF6 colocalization with the CD3 complex (rather than with CD45) enhances T cell activity. Co-immunoprecipitation identified SLAMF6-interacting proteins as those essential for TCR downstream signaling, indicating shared downstream signaling pathways. Bispecific anti-CD3/SLAMF6 antibodies designed to promote SLAMF6 clustering with CD3 enhanced T cell activation.","method":"Co-immunoprecipitation of SLAMF6 with TCR signaling proteins, bispecific antibody engineering, T cell activation assays, co-culture assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying signaling partners, antibody-based compartmentalization experiments, single lab","pmids":["36622343"],"is_preprint":false},{"year":2022,"finding":"SLAMF6/Ly108 expression on macrophages promotes M2 polarization of tumor-associated macrophages (TAMs). Ly108 siRNA silencing in macrophages suppresses M2 polarization and attenuates HCC cell migration, invasion, and tumor growth by inhibiting the NF-κB pathway.","method":"siRNA knockdown of Ly108 in THP-1 cells, murine peritoneal macrophages and bone marrow-derived macrophages, polarization marker qPCR, clonogenic and Transwell assays, murine HCC model, NF-κB pathway analysis","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple macrophage types and in vivo model, NF-κB pathway readout, single lab","pmids":["35126725"],"is_preprint":false},{"year":2025,"finding":"SLAMF6 is triggered in cis by homotypic interactions at the T cell surface (not requiring SLAMF6 on tumor cells). These cis interactions elicit inhibitory effects that suppress T cell activation and limit anti-tumor immunity. Monoclonal antibodies disrupting cis SLAMF6-SLAMF6 interactions augment T cell activation, reduce proportions of exhausted T cells, and inhibit tumor growth in vivo.","method":"In vitro cis interaction experiments, T cell activation assays with anti-SLAMF6 mAb disrupting cis interactions, in vivo tumor growth models, exhausted T cell phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic identification of cis homotypic interactions as inhibitory trigger, multiple in vitro and in vivo models, high-impact journal with rigorous experimental design","pmids":["41673151"],"is_preprint":false},{"year":2025,"finding":"Aberrant expression of SLAMF6 on primitive AML cells constitutes an immune escape mechanism. Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells. An antibody against the SLAMF6 dimerization site inhibits SLAMF6-SLAMF6 homophilic interaction and induces T cell activation and AML killing in vitro and in humanized in vivo models.","method":"SLAMF6 knockout in AML cells, T cell co-culture cytotoxicity assays, anti-SLAMF6 dimerization site antibody, humanized in vivo AML models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody targeting of specific dimerization site, multiple in vitro and in vivo readouts, single rigorous study","pmids":["41044242"],"is_preprint":false},{"year":2025,"finding":"SLAMF6 blockade impairs actin ring formation at the immunological synapse between CD8+ and CD4+ T cells, reducing CD8+-CD4+ T-cell conjugate formation and diminishing the killing efficiency of HIV-1-specific CTLs against HIV-1-infected CD4+ T cells.","method":"Anti-SLAMF6 blocking antibody, CTL-target cell conjugate assays, confocal microscopy of actin ring formation, killing efficiency assays using CTL lines from HIV+ patients","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody with imaging of actin ring, functional killing assay, preprint only (not yet peer-reviewed)","pmids":["39896504"],"is_preprint":true},{"year":2017,"finding":"Trans-Ly108 interactions between dendritic cells and iNKT cells are critical for robust iNKT cell activation. siRNA knockdown of Ly108 and peptide-blocking strategies on dendritic cells demonstrated that Ly108 co-stimulation increases iNKT cell activation; this function is conserved in human iNKT cells.","method":"siRNA knockdown of Ly108 on dendritic cells, peptide-blocking of Ly108, iNKT cell activation assays (cytokine production), human iNKT validation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown and blocking with specific activation readouts, human validation, single lab","pmids":["28373584"],"is_preprint":false},{"year":2025,"finding":"SLAMF6 expression level on immature thymocytes regulates basal TCR signaling in preselected double-positive thymocytes, influencing iNKT lineage diversity. Low SLAMF6 expression on BALB/c immature thymocytes is associated with high basal TCR signaling and iNKT2 cell expansion, while higher expression in B6 mice is associated with iNKT1 selection.","method":"Strain comparison (BALB/c vs B6), SLAMF6 expression quantification by flow cytometry, basal TCR signaling measurement in preselected DP thymocytes, iNKT subset analysis","journal":"International immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative strain comparison without direct manipulation of SLAMF6 expression level to demonstrate causality","pmids":["40405353"],"is_preprint":false},{"year":2025,"finding":"TGF-β activates SMAD3, which binds to the DNMT1 promoter and induces SLAMF6 promoter hypermethylation, silencing SLAMF6 expression in CMS4 colorectal cancer. ChIP and EMSA confirmed p-SMAD3 binding to DNMT1 promoter, establishing a TGF-β/SMAD3/DNMT1 epigenetic axis that suppresses SLAMF6.","method":"ChIP assay (p-SMAD3 binding to DNMT1 promoter), EMSA, bisulfite sequencing PCR, methylation-specific PCR, western blot for pathway components, 5-Aza treatment in tumor-bearing mice","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP and EMSA establishing direct transcription factor-promoter interaction, in vivo pharmacological validation, single lab","pmids":["41044679"],"is_preprint":false}],"current_model":"SLAMF6 (NTB-A/Ly108/CD352) is a homophilic immunoglobulin-superfamily receptor whose ectodomain (crystal structure resolved at 3.0 Å) mediates both cis (same-cell) and trans (cell-cell) homotypic interactions; cis interactions elicit inhibitory T cell signals via ITSM-dependent SHP-1 recruitment, while trans interactions can generate activating or co-stimulatory signals depending on cellular context, SAP/EAT-2 adaptor availability, and isoform expression—with the canonical receptor recruiting SAP to engage FynT and LCK for positive signaling in NKT development and NK cytotoxicity, but also recruiting SHP-1 to dampen CD3ζ phosphorylation and T cell:APC adhesion—such that its net effect oscillates between positive and negative regulation of lymphocyte activation depending on whether SAP outcompetes SHP-1 for ITSM binding, and targeting SLAMF6 cis interactions or its dimerization site with antibodies augments anti-tumor T cell immunity."},"narrative":{"mechanistic_narrative":"SLAMF6 (NTB-A/Ly108/CD352) is a self-ligand immunoglobulin-superfamily receptor that bidirectionally tunes lymphocyte activation through homophilic engagement, functioning across NK cells, T cells, NKT cells, and B cells [PMID:15162436, PMID:17045824, PMID:18031695]. It is its own ligand: chimeric Fc fusions and recombinant proteins bind only SLAMF6-expressing cells, and the 3.0 Å ectodomain structure resolves a kinked self-associating homodimer that constrains co-localization at the immunological synapse [PMID:15162436, PMID:15153464, PMID:17045824]. The receptor's net signaling output is set by which SH2-domain adaptor occupies its cytoplasmic ITSM tyrosines: SAP recruitment converts it to an activating receptor that engages FynT and LCK to amplify proximal TCR signaling, drive Th1/Th17 cytokine output, NK cytotoxicity, and restimulation-induced cell death, whereas in the absence of SAP it recruits SHP-1 to dephosphorylate CD3ζ, dampen T cell:APC adhesion, and deliver inhibitory signals [PMID:11489943, PMID:16920955, PMID:18482989, PMID:22683125, PMID:24688028, PMID:25217164]. During development, homotypic SLAMF6 interactions between thymocytes provide a SAP/Fyn-dependent co-stimulatory second signal that, via Egr-2-driven PLZF induction, is essential for NKT lineage expansion [PMID:18031695, PMID:23355739]. SLAMF6 also operates as an inhibitory checkpoint in CD8+ T cells, where its loss skews toward a T-bet-driven effector phenotype and drives durable anti-tumor immunity, and antibodies disrupting cis SLAMF6-SLAMF6 interactions or its dimerization site augment T cell activation and tumor killing [PMID:32122464, PMID:41673151, PMID:41044242]. A short splice isoform (SLAMF6Δ17-65) acts as a SHP-1-dependent agonist that imposes a cytotoxic TBX21/RUNX3 program [PMID:33762352]. The receptor is exploited and modulated by pathogens: HIV-1 Vpu sequesters NTB-A in the Golgi to block NK recognition, while influenza hemagglutinin is directly engaged in a sialylation-dependent manner to co-stimulate NK cytotoxicity [PMID:21075351, PMID:23528733, PMID:26919106].","teleology":[{"year":2001,"claim":"Established that SLAMF6 signaling polarity is controlled by adaptor availability, answering whether a single receptor could be both activating and inhibitory.","evidence":"Co-IP with SAP and SHPs plus NK cytotoxicity assays in XLP patient cells lacking SAP","pmids":["11489943"],"confidence":"High","gaps":["Did not resolve the structural basis of homophilic engagement","Relative affinities of SAP vs SHP for the ITSMs not quantified"]},{"year":2004,"claim":"Defined SLAMF6 as its own ligand, answering what engages the receptor and showing homophilic engagement drives NK effector function.","evidence":"Fc-fusion and trimeric recombinant protein binding by ELISA/SPR, surface downregulation, and NK cytotoxicity/cytokine assays","pmids":["15162436","15153464"],"confidence":"High","gaps":["Cis versus trans engagement not distinguished","Structural interface unresolved"]},{"year":2004,"claim":"Extended SLAMF6 co-stimulation to T cell biology, showing cross-linking promotes Th1 differentiation and influences B cell isotype switching and autoimmunity in vivo.","evidence":"Antibody cross-linking, SAP co-IP, cytokine ELISA, and in vivo EAE with NTB-A-Fc","pmids":["14988414"],"confidence":"Medium","gaps":["No independent replication cited","Mechanism linking SLAMF6 to isotype switching not defined"]},{"year":2006,"claim":"Provided the structural basis for homophilic recognition, answering how SLAMF6 self-associates and constrains synapse organization.","evidence":"X-ray crystallography at 3.0 Å of the full ectodomain plus analytical ultracentrifugation","pmids":["17045824"],"confidence":"High","gaps":["Structure of the cis dimer versus trans dimer not separately defined","No co-structure with adaptors or CD3"]},{"year":2006,"claim":"Mapped which ITSM tyrosine and which adaptor drive distinct outputs, separating cytotoxicity (EAT-2, second tyrosine) from IFN-γ production (SAP).","evidence":"Tyrosine mutants in NTB-A-negative NK line, SAP siRNA, co-IP, and functional NK assays","pmids":["16920955"],"confidence":"High","gaps":["Did not address SHP-1 contribution in this NK context","Constitutive phosphorylation source not directly proven to be neighboring-cell homophilic contact"]},{"year":2008,"claim":"Defined the activating biochemical pathway, showing SAP recruits FynT to drive Ly108/Vav-1/c-Cbl phosphorylation and that lupus isoform differences alter signaling strength.","evidence":"Phosphorylation assays and co-IP in SAP-null and FynT-null T cells with isoform comparison","pmids":["18482989"],"confidence":"High","gaps":["Functional consequence of isoform-specific signaling in disease not directly tested here"]},{"year":2007,"claim":"Implicated Ly108 alleles in B cell tolerance, answering whether SLAMF6 variation contributes to autoimmunity susceptibility.","evidence":"Allele-specific B cell tolerance assays in congenic mouse strains","pmids":["16778059"],"confidence":"Medium","gaps":["Molecular mechanism distinguishing the two alleles not resolved","Single lab, congenic comparison"]},{"year":2007,"claim":"Established SLAMF6 homotypic interactions as the developmental second signal for NKT lineage, defining ligand source as thymocytes not stroma.","evidence":"Slamf6, SAP, and Fyn knockout mice with thymocyte co-cultures and NKT developmental analysis","pmids":["18031695"],"confidence":"High","gaps":["Downstream transcriptional program not yet linked","Redundancy with other SLAM receptors not addressed here"]},{"year":2013,"claim":"Connected SLAMF6 co-stimulation to a transcriptional output, showing it drives PLZF via Egr-2 recruitment to the Zbtb16 promoter.","evidence":"Thymocyte co-stimulation, Egr-2 ChIP on Zbtb16 promoter, and Ly108-deficient mouse analysis","pmids":["23355739"],"confidence":"High","gaps":["Signaling steps between receptor and Egr-2 induction not fully mapped"]},{"year":2012,"claim":"Resolved the SAP/SHP-1 balance genetically, showing Ly108 deletion reverses the SAP-deficiency phenotype because it relieves SHP-1-mediated inhibition at the T:B synapse.","evidence":"Slamf6/Sh2d1a double knockout epistasis, ITSM mutagenesis, and SHP-1 recruitment assays","pmids":["22683125"],"confidence":"High","gaps":["Quantitative threshold of SAP versus SHP-1 competition not defined"]},{"year":2014,"claim":"Defined the inhibitory mechanism, showing constitutive and ligation-dependent CD3ζ dephosphorylation via SHP-1 dampens T cell-APC adhesion through the transmembrane domain.","evidence":"Proximity imaging (100-200 nm), TM-domain replacement mutants, CD3ζ phosphorylation, and adhesion assays","pmids":["25217164"],"confidence":"High","gaps":["Did not reconcile with co-stimulatory roles in the same cell types"]},{"year":2014,"claim":"Defined an activating role distinct from FynT, showing SAP recruits LCK to amplify TCR signaling and promote restimulation-induced cell death.","evidence":"LCK co-IP and kinase assays, ITSM requirement, SAP siRNA, and RICD assays in XLP T cells","pmids":["24688028"],"confidence":"High","gaps":["Whether LCK and FynT act sequentially or in parallel not resolved"]},{"year":2011,"claim":"Linked SLAMF6 co-stimulation to Th17 biology and identified the transcriptional basis, showing enhanced RORγt recruitment to the IL17A promoter beyond the CD28-shared NFAT1 effect.","evidence":"Co-stimulation assays with SAP requirement via XLP cells, plus RORγt/NFAT1 ChIP on IL17A promoter","pmids":["22184727","22989874"],"confidence":"Medium","gaps":["SLE T cell defect mechanism not fully resolved","Single lab for the ChIP mechanism"]},{"year":2011,"claim":"Demonstrated isoform-encoded regulation of autoimmunity, identifying Ly108-H1 as a disease-suppressing decoy isoform that lacks tyrosine phosphorylation.","evidence":"Transgenic overexpression in B6.Sle1b lupus model and isoform-specific phosphorylation analysis in thymi","pmids":["21422172","22393150"],"confidence":"Medium","gaps":["Structural basis of decoy behavior not defined","Human isoform correlates not established here"]},{"year":2010,"claim":"Revealed pathogen subversion, showing HIV-1 Vpu downmodulates NTB-A via its transmembrane domain and Golgi retention to evade NK recognition.","evidence":"Vpu-NTB-A co-IP, glycoform/Golgi-retention analysis, and NK degranulation assays with mutant virus","pmids":["21075351","23528733"],"confidence":"High","gaps":["Host factors mediating Golgi retention not identified"]},{"year":2016,"claim":"Established SLAMF6's role in NK cell education, showing SAP adaptors uncouple it from SHP-1 to tune responsiveness toward nonhematopoietic targets.","evidence":"SLAMF6 and SAP knockout mice, NK education assays, and hematopoietic chimeras","pmids":["26878112"],"confidence":"High","gaps":["Quantitative contribution relative to other inhibitory receptors not defined"]},{"year":2015,"claim":"Defined a redundant inhibitory module in humoral immunity, showing SLAMF1/5/6 synergistically suppress Tfh and germinal center responses.","evidence":"Triple knockout mice, adoptive co-transfer, and anti-SLAMF6 mAb treatment with GC/Tfh readouts","pmids":["25926831","27368806"],"confidence":"Medium","gaps":["Cell-intrinsic versus extrinsic contributions of each receptor not fully separated","Single lab"]},{"year":2016,"claim":"Tested redundancy in NKT development, showing combined SLAMF1/5/6 deletion worsens iNKT defects beyond SLAMF6 alone.","evidence":"CRISPR/Cas9 triple knockout mice with iNKT developmental and GC analysis","pmids":["27258160"],"confidence":"Medium","gaps":["Individual receptor contributions not isolated","Mechanism of redundancy not defined"]},{"year":2016,"claim":"Identified direct pathogen ligand recognition, showing NTB-A engages influenza hemagglutinin in a sialylation-dependent manner countered by viral neuraminidase.","evidence":"Recombinant receptor-HA binding, sialylation manipulation, NA treatment, and NK cytotoxicity assays","pmids":["26919106"],"confidence":"Medium","gaps":["Physiological contribution during in vivo infection not established"]},{"year":2015,"claim":"Extended SLAMF6 ligand binding to bacteria, showing it engages Gram-negative outer membranes and modulates mucosal inflammation.","evidence":"Reporter-based bacterial binding assay and Slamf6-/- Rag-/- Citrobacter rodentium infection model","pmids":["25957267"],"confidence":"Medium","gaps":["Bacterial ligand identity not defined","Single lab"]},{"year":2017,"claim":"Defined trans-SLAMF6 functions in cell-cell crosstalk, including DC-iNKT co-stimulation and a naive B:T MIF-CD74 survival axis.","evidence":"siRNA knockdown and peptide/antibody blocking in DC-iNKT and B-T co-cultures with XLP patient validation","pmids":["28373584","28904129"],"confidence":"Medium","gaps":["Quantitative contribution of trans versus cis interactions not separated","Single lab"]},{"year":2019,"claim":"Dissected SLAMF6 co-stimulatory requirements, showing ectodomain and tyrosine 308 dependence and adhesion enhancement via Rap1 activation upon TCR clustering.","evidence":"Domain mutants, live-cell imaging, Rap1 activation, and T cell adhesion assays","pmids":["31199820"],"confidence":"Medium","gaps":["Link between Rap1 activation and adaptor choice not resolved","Single lab"]},{"year":2020,"claim":"Established SLAMF6 as an inhibitory checkpoint in CD8+ T cells, showing its loss enables a T-bet-driven effector program and durable tumor regression.","evidence":"Pmel-1 x SLAMF6-/- mice, adoptive transfer into melanoma models, T-bet/LAG-3 phenotyping, and combination LAG-3 blockade","pmids":["32122464"],"confidence":"High","gaps":["Whether cis or trans engagement drives the inhibitory effect not resolved here"]},{"year":2021,"claim":"Showed isoform-specific function in tumor immunity, identifying SLAMF6Δ17-65 as a SHP-1-dependent agonist driving a cytotoxic TBX21/RUNX3 program targetable with splice-switching ASOs.","evidence":"Isoform cloning/comparison, SHP-1 inhibition, transcription factor analysis, and ASO testing in TILs with in vivo melanoma","pmids":["33762352"],"confidence":"High","gaps":["Endogenous regulation of isoform ratios in tumors not defined"]},{"year":2025,"claim":"Defined cis homotypic engagement as the inhibitory trigger and validated it therapeutically, showing cis-disrupting antibodies and dimerization-site antibodies augment anti-tumor T cell immunity across solid tumors and AML.","evidence":"Cis-interaction experiments and cis-disrupting/dimerization-site mAbs with in vitro and in vivo tumor and humanized AML models","pmids":["41673151","41044242"],"confidence":"High","gaps":["Structural basis distinguishing the cis-disrupting epitope from the trans interface not detailed","Combination with established checkpoint blockade not fully mapped"]},{"year":2022,"claim":"Defined SLAMF6 compartmentalization as the determinant of T cell outcome, showing CD3 (versus CD45) colocalization and bispecific-driven clustering enhance activation.","evidence":"Co-IP of SLAMF6 with TCR signaling proteins and anti-CD3/SLAMF6 bispecific antibody activation assays","pmids":["36622343"],"confidence":"Medium","gaps":["Mechanism segregating SLAMF6 from CD45 not defined","Single lab"]},{"year":2022,"claim":"Extended SLAMF6 function to myeloid cells, showing it promotes M2 tumor-associated macrophage polarization via NF-κB.","evidence":"Ly108 siRNA in multiple macrophage types, polarization markers, migration/invasion assays, and murine HCC model","pmids":["35126725"],"confidence":"Medium","gaps":["Ligand/adaptor coupling in macrophages not defined","Single lab"]},{"year":2025,"claim":"Identified transcriptional silencing of SLAMF6 in cancer, defining a TGF-β/SMAD3/DNMT1 axis that hypermethylates the SLAMF6 promoter in CMS4 colorectal cancer.","evidence":"p-SMAD3 ChIP and EMSA on DNMT1 promoter, bisulfite/methylation-specific PCR, and in vivo 5-Aza treatment","pmids":["41044679"],"confidence":"Medium","gaps":["Functional consequence of SLAMF6 silencing on anti-tumor immunity not directly tested here","Single lab"]},{"year":2025,"claim":"Implicated SLAMF6 in cytotoxic synapse organization, showing blockade impairs actin ring formation and CD8-CD4 conjugates needed for HIV-specific CTL killing.","evidence":"Anti-SLAMF6 blocking antibody, confocal imaging of actin rings, and CTL killing assays (preprint)","pmids":["39896504"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular link between SLAMF6 and actin machinery not defined"]},{"year":null,"claim":"How the competition between SAP/EAT-2 and SHP-1 at SLAMF6 ITSMs is quantitatively set in each cell type and engagement geometry (cis vs trans), and how this can be therapeutically biased toward activation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model of adaptor competition across cell types","Structural distinction between cis and trans engagement interfaces incomplete","Endogenous control of isoform ratios in disease undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,9,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,13,30]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,18,33]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,13,21,29]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[8,23,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,17,18,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,15,37]}],"complexes":[],"partners":["SLAMF6","SH2D1A","SH2D1B","FYN","LCK","PTPN6","CD3Z","VAV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DU3","full_name":"SLAM family member 6","aliases":["Activating NK receptor","NK-T-B-antigen","NTB-A"],"length_aa":332,"mass_kda":37.3,"function":"Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Triggers cytolytic activity only in natural killer cells (NK) expressing high surface densities of natural cytotoxicity receptors (PubMed:11489943, PubMed:16920955). Positive signaling in NK cells implicates phosphorylation of VAV1. NK cell activation seems to depend on SH2D1B and not on SH2D1A (PubMed:16920955). In conjunction with SLAMF1 controls the transition between positive selection and the subsequent expansion and differentiation of the thymocytic natural killer T (NKT) cell lineage (By similarity). Promotes T-cell differentiation into a helper T-cell Th17 phenotype leading to increased IL-17 secretion; the costimulatory activity requires SH2D1A (PubMed:16920955, PubMed:22184727). Promotes recruitment of RORC to the IL-17 promoter (PubMed:22989874). In conjunction with SLAMF1 and CD84/SLAMF5 may be a negative regulator of the humoral immune response. In the absence of SH2D1A/SAP can transmit negative signals to CD4(+) T-cells and NKT cells. Negatively regulates germinal center formation by inhibiting T-cell:B-cell adhesion; the function probably implicates increased association with PTPN6/SHP-1 via ITSMs in absence of SH2D1A/SAP. However, reported to be involved in maintaining B-cell tolerance in germinal centers and in preventing autoimmunity (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96DU3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLAMF6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLAMF6","total_profiled":1310},"omim":[{"mim_id":"606446","title":"SLAM FAMILY, MEMBER 6; SLAMF6","url":"https://www.omim.org/entry/606446"},{"mim_id":"604513","title":"CD84 ANTIGEN; CD84","url":"https://www.omim.org/entry/604513"},{"mim_id":"601744","title":"SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, 1; SLEB1","url":"https://www.omim.org/entry/601744"},{"mim_id":"308240","title":"LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1; XLP1","url":"https://www.omim.org/entry/308240"},{"mim_id":"300490","title":"SH2 DOMAIN PROTEIN 1A; SH2D1A","url":"https://www.omim.org/entry/300490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":57.7}],"url":"https://www.proteinatlas.org/search/SLAMF6"},"hgnc":{"alias_symbol":["KALI","NTBA","KALIb","Ly108","SF2000","NTB-A","CD352"],"prev_symbol":[]},"alphafold":{"accession":"Q96DU3","domains":[{"cath_id":"2.60.40.10","chopping":"21-128","consensus_level":"high","plddt":89.4956,"start":21,"end":128},{"cath_id":"2.60.40.10","chopping":"132-216","consensus_level":"high","plddt":91.4647,"start":132,"end":216}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DU3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DU3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DU3-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLAMF6","jax_strain_url":"https://www.jax.org/strain/search?query=SLAMF6"},"sequence":{"accession":"Q96DU3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DU3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DU3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DU3"}},"corpus_meta":[{"pmid":"18031695","id":"PMC_18031695","title":"Homotypic 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In XLP NK cells lacking SAP, NTB-A mediates inhibitory rather than activating signals, demonstrating SAP-dependent switch between activating and inhibitory signaling.\",\n      \"method\": \"Molecular cloning, tyrosine phosphorylation assays, co-immunoprecipitation with SAP and SHPs, functional NK cytotoxicity assays in XLP patient cells, antibody masking experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical co-IP, phosphorylation assay, functional assays in patient cells), foundational mechanistic paper replicated by subsequent work\",\n      \"pmids\": [\"11489943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLAMF6 (NTB-A/NTBA) is its own ligand, engaging in homophilic (self-self) interaction. A chimeric NTBA-Fc fusion protein specifically binds NTBA-expressing cells but not cells transfected with other CD2 family members, confirmed by ELISA, surface plasmon resonance (plasmon resonance analysis), and NTBA-Fc-mediated downregulation of surface NTBA expression. Homophilic engagement induces NK cell IFN-γ and TNF-α production and increases susceptibility of NTBA-expressing targets to NK-mediated killing.\",\n      \"method\": \"Chimeric Fc-fusion protein binding assay, ELISA, plasmon resonance, surface expression downregulation assay, NK cytotoxicity assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted homophilic binding in vitro using multiple orthogonal methods (SPR, ELISA, downregulation), independently confirmed by Flaig et al. 2004\",\n      \"pmids\": [\"15162436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NTB-A (SLAMF6) activates NK cells via homophilic interaction; trimeric recombinant NTB-A proteins demonstrated that NTB-A is its own ligand and that this homophilic engagement enhances NK cell cytotoxicity, proliferation, and IFN-γ secretion.\",\n      \"method\": \"Trimeric recombinant protein binding assay, NK cytotoxicity assay, proliferation assay, cytokine secretion assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution with recombinant proteins, replicates findings of Falco et al. 2004 by independent lab\",\n      \"pmids\": [\"15153464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NTB-A (SLAMF6) cross-linking in T cells induces phosphorylation of NTB-A and association with SAP, promotes T cell proliferation, IFN-γ secretion, and Th1 differentiation (not IL-4/Th2). In vivo blocking with soluble NTB-A-Fc inhibits B cell isotype switching to IgG2a/IgG3, and delays onset of experimental autoimmune encephalomyelitis in transgenic mice.\",\n      \"method\": \"Antibody cross-linking, phosphorylation assay, co-immunoprecipitation with SAP, cytokine ELISA, T cell differentiation assays, in vivo EAE model with NTB-A-Fc treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab (biochemical + in vivo), no independent replication cited\",\n      \"pmids\": [\"14988414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ly108 (SLAMF6) controls T cell cytokine responses and neutrophil bactericidal activity. Mice with targeted disruption of Ly108 exons 2 and 3 show reduced IL-4 production by CD4+ T cells and defective neutrophil bactericidal activity due to severely reduced production of reactive oxygen species following phagocytosis.\",\n      \"method\": \"Targeted gene disruption (knockout mice), in vitro cytokine assays, in vivo Leishmania infection model, Salmonella infection model, ROS production assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with specific phenotypic readouts (ROS, cytokines), single lab\",\n      \"pmids\": [\"15879084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The 3.0 Å crystal structure of the complete NTB-A (SLAMF6) ectodomain reveals a rod-like monomer that self-associates to form a highly kinked dimer spanning ~100 Å end-to-end. The NTB-A homophilic dimer shows overall structural similarity to CD2-CD58 heterophilic dimer but differs in detailed interface organization. The structure suggests a mechanism for binding specificity within the SLAM family and imposes constraints on colocalization with other signaling molecules at the immunological synapse.\",\n      \"method\": \"X-ray crystallography at 3.0 Å resolution, analytical ultracentrifugation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional interpretation, rigorous single study with structural validation\",\n      \"pmids\": [\"17045824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NTB-A (SLAMF6) is constitutively tyrosine phosphorylated in unstimulated human NK cells by Src family kinases, likely due to homophilic interaction among neighboring NK cells. The cytoplasmic tail contains three tyrosines in immunoreceptor tyrosine-based switch motifs; the second tyrosine is sufficient and essential for NTB-A-mediated cytotoxicity. EAT-2 (not SAP) is recruited to this second tyrosine for cytotoxicity, while SAP is required for IFN-γ production, demonstrating that cytokine production and cytotoxicity are differentially dependent on SAP versus EAT-2.\",\n      \"method\": \"NTB-A tyrosine mutant expression in NTB-A-negative NK cell line, SAP knockdown by siRNA, functional cytotoxicity and cytokine assays, co-immunoprecipitation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis of tyrosine residues, genetic knockdown, multiple functional readouts, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"16920955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Ly108.2 allele (normal), but not the lupus-associated Ly108.1 allele, sensitizes immature B cells to deletion and RAG reexpression, establishing Ly108 (SLAMF6) as a regulator of B cell tolerance checkpoints.\",\n      \"method\": \"Allele-specific expression analysis, B cell tolerance assays (anergy, deletion, receptor revision) in congenic mouse strains\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific functional comparison in congenic strains, single lab, specific B cell tolerance readouts\",\n      \"pmids\": [\"16778059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homotypic interactions mediated by Slamf1 and Slamf6 (Ly108) generate co-stimulatory 'second signals' downstream of TCR engagement during T-T (thymocyte-thymocyte) interactions; these signals recruit SAP and Src kinase Fyn and are essential for NKT cell lineage expansion and differentiation. Ligand recognition on thymocytes (which express Slamf6) but not stromal epithelial cells (which do not) determines the availability of this co-signaling pathway.\",\n      \"method\": \"Genetic mouse models (Slamf6 knockout, SAP knockout, Fyn knockout), thymocyte co-culture assays, NKT cell developmental analysis by flow cytometry\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis using multiple genetic knockouts, replicated across several receptor/adaptor/kinase knockouts, specific developmental readouts\",\n      \"pmids\": [\"18031695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ly108 (SLAMF6) mediates tyrosine phosphorylation signals in T cells implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on SAP co-expression and extracellular domain engagement. SAP recruits FynT to mediate this phosphorylation. The lupus-associated isoform Ly108-1 more potently triggers tyrosine phosphorylation than the non-lupus Ly108-2 isoform, partly due to a unique intracytoplasmic tyrosine-based motif in Ly108-1.\",\n      \"method\": \"Tyrosine phosphorylation assays, co-immunoprecipitation, analysis of SAP-FynT pathway mutant T cells, isoform comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution with multiple genetic controls (SAP-null, FynT-null mice), isoform mutagenesis comparison, single rigorous lab study\",\n      \"pmids\": [\"18482989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HIV-1 Vpu downmodulates NTB-A (SLAMF6) on infected CD4+ T cells, associating with NTB-A through its transmembrane region without promoting NTB-A degradation. This prevents homophilic NTB-A engagement between NK cells and infected targets, thereby reducing NK cell degranulation. Cells infected with Vpu mutant virus elicited at least 50% more NK cells to degranulate than wild-type virus.\",\n      \"method\": \"Co-immunoprecipitation of Vpu with NTB-A, flow cytometry of surface NTB-A, NK degranulation assays, Vpu mutant virus comparison\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct co-IP identifying Vpu-NTB-A interaction via transmembrane domain, functional degranulation assays, mutant virus controls\",\n      \"pmids\": [\"21075351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLAMF6 co-engagement with CD3 under Th17-polarizing conditions increases IL-17 production in a SAP-dependent manner. SLAMF3/SLAMF6 co-stimulation is more potent and prolonged than CD28 co-stimulation for IL-17 induction in both naive and memory CD4+ T cells from normal donors, but is defective in SLE T cells.\",\n      \"method\": \"Antibody co-stimulation assays, intracellular cytokine staining, correlation with disease activity, SAP requirement established by comparison with XLP patients\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-stimulation assays with SAP requirement established via XLP patient cells, single lab, multiple patient cohorts\",\n      \"pmids\": [\"22184727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Ly108-H1 isoform of SLAMF6, absent in lupus-prone congenic mice, suppresses T cell-dependent autoimmunity. Introduction of an Ly108-H1-expressing transgene markedly diminishes autoantibody production and T cell-driven pathology in B6.Sle1b mice, identifying this isoform as a disease-suppressing regulatory form.\",\n      \"method\": \"Transgenic mouse overexpression, autoantibody assays, in vivo lupus model (B6.Sle1b congenic)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic rescue experiment in congenic disease model, single lab, specific functional readout\",\n      \"pmids\": [\"21422172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of Ly108 (Slamf6) in CD4+ T cells reverses the SAP-deficiency phenotype, eliminating the SAP requirement for germinal centers. Ly108 exerts potent negative signaling requiring ITSMs and SHP-1 recruitment, resulting in high SHP-1 at the T cell:B cell synapse, limiting T cell:B cell adhesion. SLAMF6-negative signaling also contributes to NKT cell differentiation defect in SAP-null mice.\",\n      \"method\": \"Genetic epistasis (Slamf6-/-/Sh2d1a-/- double knockout mice), germinal center analysis, NKT cell developmental assays, ITSM mutagenesis, SHP-1 recruitment assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic epistasis with double KO, ITSM mutagenesis, multiple orthogonal functional readouts, single rigorous study\",\n      \"pmids\": [\"22683125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ly108 (SLAMF6) is constitutively tyrosine phosphorylated in murine thymi in a SAP- and Fyn kinase-dependent manner. Phosphorylation is dynamically regulated by cell-cell contact (lost rapidly after thymocyte disaggregation). Distinct isoforms are differentially expressed in lupus-resistant versus lupus-prone mouse strains; the Ly108-H1 isoform does not undergo tyrosine phosphorylation, suggesting it functions as a decoy isoform.\",\n      \"method\": \"Tyrosine phosphorylation analysis of thymic lysates, disaggregation kinetics, isoform-specific expression analysis, comparison of SAP-null and Fyn-null mice\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical analysis with genetic controls (SAP-null, Fyn-null), isoform-specific phosphorylation, single lab\",\n      \"pmids\": [\"22393150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ly108 (SLAMF6) co-stimulation of double-positive thymocytes markedly enhances expression of the transcription factor PLZF (encoded by Zbtb16) compared to TCR stimulation alone. This is mediated through increased Egr-2 expression and enhanced Egr-2 binding to the Zbtb16 promoter; CD28 co-stimulation failed to enhance Egr-2 binding or PLZF levels. Ly108-deficient mice show decreased numbers of PLZF-expressing CD4+ T cells.\",\n      \"method\": \"Thymocyte co-stimulation assays, ChIP assay (Egr-2 binding to Zbtb16 promoter), flow cytometry, Ly108-deficient mouse analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP assay establishing direct transcription factor recruitment, KO mouse confirmation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23355739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIV-1 Vpu prevents formation of the mature glycoform of NTB-A (SLAMF6) by retaining NTB-A within the Golgi compartment; only the high-mannose (immature) form is detectable in the presence of Vpu. This mechanism is distinct from Vpu-mediated downregulation of CD4 and tetherin and is highly conserved among HIV-1 and SIV Vpu proteins.\",\n      \"method\": \"Glycosylation analysis (EndoH/PNGaseF digestion), immunofluorescence/confocal microscopy for Golgi retention, comparison of multiple Vpu variants\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical glycosylation analysis with subcellular localization imaging, single lab, multiple Vpu variants tested\",\n      \"pmids\": [\"23528733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SAP facilitates recruitment and activation of LCK (but not FYN) at NTB-A (SLAMF6) receptors in activated T cells. Upon TCR restimulation, LCK association with NTB-A increases in a SAP-dependent manner, requiring both ITSMs in the NTB-A cytoplasmic tail. NTB-A-associated LCK phosphorylation and kinase activity are enhanced, amplifying proximal TCR signaling and promoting restimulation-induced cell death (RICD). In XLP T cells (SAP-null), this association and RICD are reduced.\",\n      \"method\": \"Co-immunoprecipitation of LCK with NTB-A, LCK kinase activity assay, RICD assay, ITSM requirement analysis, SAP siRNA knockdown, XLP patient T cells\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP with kinase activity assay, genetic controls (XLP patient cells, SAP siRNA), ITSM requirement, multiple orthogonal methods\",\n      \"pmids\": [\"24688028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ly108 (SLAMF6) dampens T cell adhesion to antigen-presenting B cells and dendritic cells by inhibiting CD3ζ phosphorylation through two mechanisms: (1) constitutive colocalization with CD3 complex within 100-200 nm on quiescent cells reducing CD3ζ phosphorylation independent of ligation; (2) ligation-dependent Ly108-CD3ζ interaction promoted by Ly108 transmembrane domain leading to more efficient CD3ζ dephosphorylation via constitutively associated SHP-1. Replacement of Ly108 TM domain abrogates ligation-dependent inhibition and suppression of T-B adhesion.\",\n      \"method\": \"FRET/imaging within 100-200 nm, transmembrane domain replacement mutants, CD3ζ phosphorylation assay, T cell-APC adhesion assay, SHP-1 co-immunoprecipitation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mutants with specific phosphorylation readouts, proximity imaging, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25217164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF1, SLAMF5, and SLAMF6 act synergistically as negative regulators of humoral immunity. Adoptive co-transfer experiments showed that [Slamf1+5+6]-/- B cells (more than T cells) drive enhanced antibody responses; anti-SLAMF6 monoclonal antibody severely inhibits Tfh cell and germinal center B cell development, confirming SLAMF6's suppressive role in humoral responses.\",\n      \"method\": \"Triple knockout mice, T-independent and T-dependent antibody assays, adoptive co-transfer experiments, anti-SLAMF6 mAb treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and antibody-mediated loss-of-function with specific GC/Tfh readouts, single lab, multiple experimental approaches\",\n      \"pmids\": [\"25926831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF6 (Slamf6) engages structures on the outer cell membrane of several Gram-negative bacteria (demonstrated by reporter-based binding assay), and Slamf6-mediated interactions of colonic innate immune cells with specific Gram-negative bacteria reduce mucosal protection and enhance inflammation; Slamf6 deficiency in Rag-/- mice reduces inflammatory pathology and bacterial translocation during Citrobacter rodentium infection, while enhancing IL-22 production.\",\n      \"method\": \"Reporter-based bacterial binding assay, Slamf6-/- Rag-/- mouse infection model, anti-Slamf6 mAb blocking of bacterial interactions, cytokine analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus in vivo KO model with specific immune readouts, single lab\",\n      \"pmids\": [\"25957267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLAMF6 on NK cells, together with SAP family adaptors and SHP-1 phosphatase, regulates NK cell education. SLAMF6 expressed on hematopoietic cells enhances NK cell activation by nonhematopoietic target cells (which lack SLAM receptor ligands); SAP adaptors uncouple SLAM receptors from SHP-1, diminishing SLAMF6's effect on NK cell responsiveness toward nonhematopoietic cells.\",\n      \"method\": \"SLAMF6 knockout mice, SAP adaptor knockout mice, NK cell education assays, hematopoietic chimera experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection with multiple KO models, hematopoietic chimeras, rigorous mechanistic epistasis, high-impact journal\",\n      \"pmids\": [\"26878112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transfer of Slamf6-/- CD4+ T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated autoantibodies, Tfh cells, IFN-γ-producing CD4+ cells, and GC B cells. This pathology requires Slamf1 co-expression (Slamf[1+6]-/- cells did not induce increased autoantibodies), placing SLAMF6 as an inhibitory receptor whose absence, in combination with Slamf1, drives autoimmune responses. The Slamf6-H1 isoform expressed in Slamf6-/- T cells did not induce this phenotype.\",\n      \"method\": \"Adoptive transfer of KO T cells, flow cytometry for Tfh/GC B cells, autoantibody ELISA, double KO epistasis\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with adoptive transfer, specific autoimmune readouts, single lab\",\n      \"pmids\": [\"27368806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Naive B and T cells interact via homophilic SLAMF6 engagement at their surface, generating cell-type-specific SAP-dependent signals: T cells upregulate migration inhibitory factor (MIF), while B cells upregulate CD74 (MIF receptor), consequently enhancing B cell survival. In XLP patients (SAP-deficient), this interaction is disrupted, reducing CD74 expression and impairing naive B cell maintenance.\",\n      \"method\": \"Co-culture of naive B and T cells, antibody blocking of SLAMF6, cytokine/receptor expression analysis, XLP patient cells, SAP-null comparison\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-cell interaction assay with blocking antibody and XLP patient validation, identification of MIF-CD74 axis, single lab\",\n      \"pmids\": [\"28904129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD3-T cell receptor co-stimulation through SLAMF3 and SLAMF6 enhances recruitment of RORγt to the IL17A promoter in human T lymphocytes, beyond the effect of NFAT1 recruitment that is shared with CD28 co-stimulation. The dominance of SLAMF3/SLAMF6 pathway in IL-17A induction is attributed to increased nuclear abundance and IL17A promoter binding of RORγt.\",\n      \"method\": \"ChIP assay for NFAT1 and RORγt binding to IL17A promoter, nuclear fractionation, co-stimulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP assay establishing direct transcription factor recruitment to promoter, single lab\",\n      \"pmids\": [\"22989874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NK cell cytotoxicity mediated by NTB-A (SLAMF6) is SAP-dependent, but the role of SAP is downstream of receptor phosphorylation and lipid raft recruitment (both of which are unaffected by SAP loss). EAT-2 recruitment to NTB-A is abrogated in the absence of SAP, revealing cooperativity between SAP and EAT-2 adaptors.\",\n      \"method\": \"SAP knockdown in primary NK cells, raft recruitment analysis, phosphorylation assay, EAT-2 knockdown, cytotoxicity assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with specific signaling dissection, multiple readouts, single lab\",\n      \"pmids\": [\"23346089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Using CRISPR/Cas9 to generate triple knockout (SLAMF1/SLAMF5/SLAMF6 TKO) mice, combined deletion worsened iNKT cell developmental defects compared to SLAMF6 single knockout, supporting positive signaling roles and potential redundancy among these receptors in iNKT cell development. Germinal center formation was only mildly defective in TKO mice.\",\n      \"method\": \"CRISPR/Cas9 triple gene knockout, iNKT cell developmental analysis by flow cytometry, germinal center analysis post-immunization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with CRISPR triple KO, specific iNKT developmental readout, single lab\",\n      \"pmids\": [\"27258160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"2B4 and NTB-A (SLAMF6) directly recognize influenza viral hemagglutinin (HA) protein on infected cells, co-stimulating NK cell cytotoxicity. These interactions require sialylation of the receptors. The virus neuraminidase (NA) protein counters these interactions by desialylating the receptors.\",\n      \"method\": \"Direct binding assays between recombinant receptors and HA, sialylation dependency experiments, NA treatment, NK cytotoxicity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding assays with recombinant proteins, sialylation manipulation, single lab\",\n      \"pmids\": [\"26919106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLAMF6 functions as a co-stimulatory receptor requiring its ectodomain for function (but not for recruitment to the immunological synapse); tyrosine 308 in the cytoplasmic tail is crucial for T cell activation enhancement. SLAMF6 clustering with the TCR (demonstrated by imaging) dramatically increases downstream signaling. SLAMF6 enhances T cell function by increasing T cell adhesiveness through activation of the small GTPase Rap1.\",\n      \"method\": \"Biochemical and genetic experiments (SLAMF6 domain mutants), flow cytometry, live-cell imaging, Rap1 activation assay, T cell adhesion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (domain mutants, imaging, GTPase assay), single lab\",\n      \"pmids\": [\"31199820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLAMF6 deficiency in CD8+ T cells augments anti-tumor cytolysis and skews toward an effector phenotype with T-bet as the dominant transcription factor. Adoptive transfer of SLAMF6-/- Pmel-1 T cells to melanoma-bearing mice results in lasting tumor regression. SLAMF6 absence increases LAG-3 expression on CD8+ T cells, and combinatorial LAG-3 blockade further improves anti-tumor responses, establishing SLAMF6 as an inhibitory immune checkpoint for CD8+ T cells.\",\n      \"method\": \"Pmel-1 x SLAMF6-/- mouse generation, adoptive transfer into melanoma models (B16, Eμ-TCL1), flow cytometry for T cell phenotype, transcription factor analysis (T-bet), degranulation assays, combination antibody treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo tumor models, multiple functional readouts, mechanistic transcription factor analysis, single rigorous multi-experiment study\",\n      \"pmids\": [\"32122464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLAMF6 has three splice isoforms involving its V-domain in humans. The canonical receptor inhibits T cell activation through SAP recruitment, while the short isoform SLAMF6Δ17-65 has strong agonistic/costimulatory effects. The costimulatory action of SLAMF6Δ17-65 is SHP-1-dependent and leads to a cytotoxic molecular profile mediated by expression of TBX21 and RUNX3. Splice-switching antisense oligonucleotides (ASOs) targeting the SLAMF6 splice junction enhance SLAMF6Δ17-65 expression in TILs and improve their anti-melanoma capacity in mice.\",\n      \"method\": \"Isoform cloning and expression, T cell activation assays comparing isoforms, SHP-1 inhibitor experiments, transcription factor analysis, ASO design and testing in TILs, in vivo melanoma model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — isoform-specific functional comparison with mechanistic follow-up (SHP-1 dependence, transcription factors), in vivo confirmation, single rigorous multi-experiment study\",\n      \"pmids\": [\"33762352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLAMF6 colocalization with the CD3 complex (rather than with CD45) enhances T cell activity. Co-immunoprecipitation identified SLAMF6-interacting proteins as those essential for TCR downstream signaling, indicating shared downstream signaling pathways. Bispecific anti-CD3/SLAMF6 antibodies designed to promote SLAMF6 clustering with CD3 enhanced T cell activation.\",\n      \"method\": \"Co-immunoprecipitation of SLAMF6 with TCR signaling proteins, bispecific antibody engineering, T cell activation assays, co-culture assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying signaling partners, antibody-based compartmentalization experiments, single lab\",\n      \"pmids\": [\"36622343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLAMF6/Ly108 expression on macrophages promotes M2 polarization of tumor-associated macrophages (TAMs). Ly108 siRNA silencing in macrophages suppresses M2 polarization and attenuates HCC cell migration, invasion, and tumor growth by inhibiting the NF-κB pathway.\",\n      \"method\": \"siRNA knockdown of Ly108 in THP-1 cells, murine peritoneal macrophages and bone marrow-derived macrophages, polarization marker qPCR, clonogenic and Transwell assays, murine HCC model, NF-κB pathway analysis\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple macrophage types and in vivo model, NF-κB pathway readout, single lab\",\n      \"pmids\": [\"35126725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAMF6 is triggered in cis by homotypic interactions at the T cell surface (not requiring SLAMF6 on tumor cells). These cis interactions elicit inhibitory effects that suppress T cell activation and limit anti-tumor immunity. Monoclonal antibodies disrupting cis SLAMF6-SLAMF6 interactions augment T cell activation, reduce proportions of exhausted T cells, and inhibit tumor growth in vivo.\",\n      \"method\": \"In vitro cis interaction experiments, T cell activation assays with anti-SLAMF6 mAb disrupting cis interactions, in vivo tumor growth models, exhausted T cell phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic identification of cis homotypic interactions as inhibitory trigger, multiple in vitro and in vivo models, high-impact journal with rigorous experimental design\",\n      \"pmids\": [\"41673151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Aberrant expression of SLAMF6 on primitive AML cells constitutes an immune escape mechanism. Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells. An antibody against the SLAMF6 dimerization site inhibits SLAMF6-SLAMF6 homophilic interaction and induces T cell activation and AML killing in vitro and in humanized in vivo models.\",\n      \"method\": \"SLAMF6 knockout in AML cells, T cell co-culture cytotoxicity assays, anti-SLAMF6 dimerization site antibody, humanized in vivo AML models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody targeting of specific dimerization site, multiple in vitro and in vivo readouts, single rigorous study\",\n      \"pmids\": [\"41044242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAMF6 blockade impairs actin ring formation at the immunological synapse between CD8+ and CD4+ T cells, reducing CD8+-CD4+ T-cell conjugate formation and diminishing the killing efficiency of HIV-1-specific CTLs against HIV-1-infected CD4+ T cells.\",\n      \"method\": \"Anti-SLAMF6 blocking antibody, CTL-target cell conjugate assays, confocal microscopy of actin ring formation, killing efficiency assays using CTL lines from HIV+ patients\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody with imaging of actin ring, functional killing assay, preprint only (not yet peer-reviewed)\",\n      \"pmids\": [\"39896504\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Trans-Ly108 interactions between dendritic cells and iNKT cells are critical for robust iNKT cell activation. siRNA knockdown of Ly108 and peptide-blocking strategies on dendritic cells demonstrated that Ly108 co-stimulation increases iNKT cell activation; this function is conserved in human iNKT cells.\",\n      \"method\": \"siRNA knockdown of Ly108 on dendritic cells, peptide-blocking of Ly108, iNKT cell activation assays (cytokine production), human iNKT validation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown and blocking with specific activation readouts, human validation, single lab\",\n      \"pmids\": [\"28373584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAMF6 expression level on immature thymocytes regulates basal TCR signaling in preselected double-positive thymocytes, influencing iNKT lineage diversity. Low SLAMF6 expression on BALB/c immature thymocytes is associated with high basal TCR signaling and iNKT2 cell expansion, while higher expression in B6 mice is associated with iNKT1 selection.\",\n      \"method\": \"Strain comparison (BALB/c vs B6), SLAMF6 expression quantification by flow cytometry, basal TCR signaling measurement in preselected DP thymocytes, iNKT subset analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative strain comparison without direct manipulation of SLAMF6 expression level to demonstrate causality\",\n      \"pmids\": [\"40405353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β activates SMAD3, which binds to the DNMT1 promoter and induces SLAMF6 promoter hypermethylation, silencing SLAMF6 expression in CMS4 colorectal cancer. ChIP and EMSA confirmed p-SMAD3 binding to DNMT1 promoter, establishing a TGF-β/SMAD3/DNMT1 epigenetic axis that suppresses SLAMF6.\",\n      \"method\": \"ChIP assay (p-SMAD3 binding to DNMT1 promoter), EMSA, bisulfite sequencing PCR, methylation-specific PCR, western blot for pathway components, 5-Aza treatment in tumor-bearing mice\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP and EMSA establishing direct transcription factor-promoter interaction, in vivo pharmacological validation, single lab\",\n      \"pmids\": [\"41044679\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLAMF6 (NTB-A/Ly108/CD352) is a homophilic immunoglobulin-superfamily receptor whose ectodomain (crystal structure resolved at 3.0 Å) mediates both cis (same-cell) and trans (cell-cell) homotypic interactions; cis interactions elicit inhibitory T cell signals via ITSM-dependent SHP-1 recruitment, while trans interactions can generate activating or co-stimulatory signals depending on cellular context, SAP/EAT-2 adaptor availability, and isoform expression—with the canonical receptor recruiting SAP to engage FynT and LCK for positive signaling in NKT development and NK cytotoxicity, but also recruiting SHP-1 to dampen CD3ζ phosphorylation and T cell:APC adhesion—such that its net effect oscillates between positive and negative regulation of lymphocyte activation depending on whether SAP outcompetes SHP-1 for ITSM binding, and targeting SLAMF6 cis interactions or its dimerization site with antibodies augments anti-tumor T cell immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLAMF6 (NTB-A/Ly108/CD352) is a self-ligand immunoglobulin-superfamily receptor that bidirectionally tunes lymphocyte activation through homophilic engagement, functioning across NK cells, T cells, NKT cells, and B cells [#1, #5, #8]. It is its own ligand: chimeric Fc fusions and recombinant proteins bind only SLAMF6-expressing cells, and the 3.0 \\u00c5 ectodomain structure resolves a kinked self-associating homodimer that constrains co-localization at the immunological synapse [#1, #2, #5]. The receptor's net signaling output is set by which SH2-domain adaptor occupies its cytoplasmic ITSM tyrosines: SAP recruitment converts it to an activating receptor that engages FynT and LCK to amplify proximal TCR signaling, drive Th1/Th17 cytokine output, NK cytotoxicity, and restimulation-induced cell death, whereas in the absence of SAP it recruits SHP-1 to dephosphorylate CD3\\u03b6, dampen T cell:APC adhesion, and deliver inhibitory signals [#0, #6, #9, #13, #17, #18]. During development, homotypic SLAMF6 interactions between thymocytes provide a SAP/Fyn-dependent co-stimulatory second signal that, via Egr-2-driven PLZF induction, is essential for NKT lineage expansion [#8, #15]. SLAMF6 also operates as an inhibitory checkpoint in CD8+ T cells, where its loss skews toward a T-bet-driven effector phenotype and drives durable anti-tumor immunity, and antibodies disrupting cis SLAMF6-SLAMF6 interactions or its dimerization site augment T cell activation and tumor killing [#29, #33, #34]. A short splice isoform (SLAMF6\\u039417-65) acts as a SHP-1-dependent agonist that imposes a cytotoxic TBX21/RUNX3 program [#30]. The receptor is exploited and modulated by pathogens: HIV-1 Vpu sequesters NTB-A in the Golgi to block NK recognition, while influenza hemagglutinin is directly engaged in a sialylation-dependent manner to co-stimulate NK cytotoxicity [#10, #16, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that SLAMF6 signaling polarity is controlled by adaptor availability, answering whether a single receptor could be both activating and inhibitory.\",\n      \"evidence\": \"Co-IP with SAP and SHPs plus NK cytotoxicity assays in XLP patient cells lacking SAP\",\n      \"pmids\": [\"11489943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of homophilic engagement\", \"Relative affinities of SAP vs SHP for the ITSMs not quantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined SLAMF6 as its own ligand, answering what engages the receptor and showing homophilic engagement drives NK effector function.\",\n      \"evidence\": \"Fc-fusion and trimeric recombinant protein binding by ELISA/SPR, surface downregulation, and NK cytotoxicity/cytokine assays\",\n      \"pmids\": [\"15162436\", \"15153464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis versus trans engagement not distinguished\", \"Structural interface unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended SLAMF6 co-stimulation to T cell biology, showing cross-linking promotes Th1 differentiation and influences B cell isotype switching and autoimmunity in vivo.\",\n      \"evidence\": \"Antibody cross-linking, SAP co-IP, cytokine ELISA, and in vivo EAE with NTB-A-Fc\",\n      \"pmids\": [\"14988414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication cited\", \"Mechanism linking SLAMF6 to isotype switching not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural basis for homophilic recognition, answering how SLAMF6 self-associates and constrains synapse organization.\",\n      \"evidence\": \"X-ray crystallography at 3.0 \\u00c5 of the full ectodomain plus analytical ultracentrifugation\",\n      \"pmids\": [\"17045824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the cis dimer versus trans dimer not separately defined\", \"No co-structure with adaptors or CD3\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped which ITSM tyrosine and which adaptor drive distinct outputs, separating cytotoxicity (EAT-2, second tyrosine) from IFN-\\u03b3 production (SAP).\",\n      \"evidence\": \"Tyrosine mutants in NTB-A-negative NK line, SAP siRNA, co-IP, and functional NK assays\",\n      \"pmids\": [\"16920955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address SHP-1 contribution in this NK context\", \"Constitutive phosphorylation source not directly proven to be neighboring-cell homophilic contact\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the activating biochemical pathway, showing SAP recruits FynT to drive Ly108/Vav-1/c-Cbl phosphorylation and that lupus isoform differences alter signaling strength.\",\n      \"evidence\": \"Phosphorylation assays and co-IP in SAP-null and FynT-null T cells with isoform comparison\",\n      \"pmids\": [\"18482989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of isoform-specific signaling in disease not directly tested here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Implicated Ly108 alleles in B cell tolerance, answering whether SLAMF6 variation contributes to autoimmunity susceptibility.\",\n      \"evidence\": \"Allele-specific B cell tolerance assays in congenic mouse strains\",\n      \"pmids\": [\"16778059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism distinguishing the two alleles not resolved\", \"Single lab, congenic comparison\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established SLAMF6 homotypic interactions as the developmental second signal for NKT lineage, defining ligand source as thymocytes not stroma.\",\n      \"evidence\": \"Slamf6, SAP, and Fyn knockout mice with thymocyte co-cultures and NKT developmental analysis\",\n      \"pmids\": [\"18031695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program not yet linked\", \"Redundancy with other SLAM receptors not addressed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected SLAMF6 co-stimulation to a transcriptional output, showing it drives PLZF via Egr-2 recruitment to the Zbtb16 promoter.\",\n      \"evidence\": \"Thymocyte co-stimulation, Egr-2 ChIP on Zbtb16 promoter, and Ly108-deficient mouse analysis\",\n      \"pmids\": [\"23355739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling steps between receptor and Egr-2 induction not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the SAP/SHP-1 balance genetically, showing Ly108 deletion reverses the SAP-deficiency phenotype because it relieves SHP-1-mediated inhibition at the T:B synapse.\",\n      \"evidence\": \"Slamf6/Sh2d1a double knockout epistasis, ITSM mutagenesis, and SHP-1 recruitment assays\",\n      \"pmids\": [\"22683125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of SAP versus SHP-1 competition not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the inhibitory mechanism, showing constitutive and ligation-dependent CD3\\u03b6 dephosphorylation via SHP-1 dampens T cell-APC adhesion through the transmembrane domain.\",\n      \"evidence\": \"Proximity imaging (100-200 nm), TM-domain replacement mutants, CD3\\u03b6 phosphorylation, and adhesion assays\",\n      \"pmids\": [\"25217164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile with co-stimulatory roles in the same cell types\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined an activating role distinct from FynT, showing SAP recruits LCK to amplify TCR signaling and promote restimulation-induced cell death.\",\n      \"evidence\": \"LCK co-IP and kinase assays, ITSM requirement, SAP siRNA, and RICD assays in XLP T cells\",\n      \"pmids\": [\"24688028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LCK and FynT act sequentially or in parallel not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked SLAMF6 co-stimulation to Th17 biology and identified the transcriptional basis, showing enhanced ROR\\u03b3t recruitment to the IL17A promoter beyond the CD28-shared NFAT1 effect.\",\n      \"evidence\": \"Co-stimulation assays with SAP requirement via XLP cells, plus ROR\\u03b3t/NFAT1 ChIP on IL17A promoter\",\n      \"pmids\": [\"22184727\", \"22989874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SLE T cell defect mechanism not fully resolved\", \"Single lab for the ChIP mechanism\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated isoform-encoded regulation of autoimmunity, identifying Ly108-H1 as a disease-suppressing decoy isoform that lacks tyrosine phosphorylation.\",\n      \"evidence\": \"Transgenic overexpression in B6.Sle1b lupus model and isoform-specific phosphorylation analysis in thymi\",\n      \"pmids\": [\"21422172\", \"22393150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of decoy behavior not defined\", \"Human isoform correlates not established here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed pathogen subversion, showing HIV-1 Vpu downmodulates NTB-A via its transmembrane domain and Golgi retention to evade NK recognition.\",\n      \"evidence\": \"Vpu-NTB-A co-IP, glycoform/Golgi-retention analysis, and NK degranulation assays with mutant virus\",\n      \"pmids\": [\"21075351\", \"23528733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host factors mediating Golgi retention not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SLAMF6's role in NK cell education, showing SAP adaptors uncouple it from SHP-1 to tune responsiveness toward nonhematopoietic targets.\",\n      \"evidence\": \"SLAMF6 and SAP knockout mice, NK education assays, and hematopoietic chimeras\",\n      \"pmids\": [\"26878112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to other inhibitory receptors not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a redundant inhibitory module in humoral immunity, showing SLAMF1/5/6 synergistically suppress Tfh and germinal center responses.\",\n      \"evidence\": \"Triple knockout mice, adoptive co-transfer, and anti-SLAMF6 mAb treatment with GC/Tfh readouts\",\n      \"pmids\": [\"25926831\", \"27368806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic versus extrinsic contributions of each receptor not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Tested redundancy in NKT development, showing combined SLAMF1/5/6 deletion worsens iNKT defects beyond SLAMF6 alone.\",\n      \"evidence\": \"CRISPR/Cas9 triple knockout mice with iNKT developmental and GC analysis\",\n      \"pmids\": [\"27258160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual receptor contributions not isolated\", \"Mechanism of redundancy not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified direct pathogen ligand recognition, showing NTB-A engages influenza hemagglutinin in a sialylation-dependent manner countered by viral neuraminidase.\",\n      \"evidence\": \"Recombinant receptor-HA binding, sialylation manipulation, NA treatment, and NK cytotoxicity assays\",\n      \"pmids\": [\"26919106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contribution during in vivo infection not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SLAMF6 ligand binding to bacteria, showing it engages Gram-negative outer membranes and modulates mucosal inflammation.\",\n      \"evidence\": \"Reporter-based bacterial binding assay and Slamf6-/- Rag-/- Citrobacter rodentium infection model\",\n      \"pmids\": [\"25957267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bacterial ligand identity not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined trans-SLAMF6 functions in cell-cell crosstalk, including DC-iNKT co-stimulation and a naive B:T MIF-CD74 survival axis.\",\n      \"evidence\": \"siRNA knockdown and peptide/antibody blocking in DC-iNKT and B-T co-cultures with XLP patient validation\",\n      \"pmids\": [\"28373584\", \"28904129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of trans versus cis interactions not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected SLAMF6 co-stimulatory requirements, showing ectodomain and tyrosine 308 dependence and adhesion enhancement via Rap1 activation upon TCR clustering.\",\n      \"evidence\": \"Domain mutants, live-cell imaging, Rap1 activation, and T cell adhesion assays\",\n      \"pmids\": [\"31199820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between Rap1 activation and adaptor choice not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established SLAMF6 as an inhibitory checkpoint in CD8+ T cells, showing its loss enables a T-bet-driven effector program and durable tumor regression.\",\n      \"evidence\": \"Pmel-1 x SLAMF6-/- mice, adoptive transfer into melanoma models, T-bet/LAG-3 phenotyping, and combination LAG-3 blockade\",\n      \"pmids\": [\"32122464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cis or trans engagement drives the inhibitory effect not resolved here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed isoform-specific function in tumor immunity, identifying SLAMF6\\u039417-65 as a SHP-1-dependent agonist driving a cytotoxic TBX21/RUNX3 program targetable with splice-switching ASOs.\",\n      \"evidence\": \"Isoform cloning/comparison, SHP-1 inhibition, transcription factor analysis, and ASO testing in TILs with in vivo melanoma\",\n      \"pmids\": [\"33762352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of isoform ratios in tumors not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined cis homotypic engagement as the inhibitory trigger and validated it therapeutically, showing cis-disrupting antibodies and dimerization-site antibodies augment anti-tumor T cell immunity across solid tumors and AML.\",\n      \"evidence\": \"Cis-interaction experiments and cis-disrupting/dimerization-site mAbs with in vitro and in vivo tumor and humanized AML models\",\n      \"pmids\": [\"41673151\", \"41044242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis distinguishing the cis-disrupting epitope from the trans interface not detailed\", \"Combination with established checkpoint blockade not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined SLAMF6 compartmentalization as the determinant of T cell outcome, showing CD3 (versus CD45) colocalization and bispecific-driven clustering enhance activation.\",\n      \"evidence\": \"Co-IP of SLAMF6 with TCR signaling proteins and anti-CD3/SLAMF6 bispecific antibody activation assays\",\n      \"pmids\": [\"36622343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism segregating SLAMF6 from CD45 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SLAMF6 function to myeloid cells, showing it promotes M2 tumor-associated macrophage polarization via NF-\\u03baB.\",\n      \"evidence\": \"Ly108 siRNA in multiple macrophage types, polarization markers, migration/invasion assays, and murine HCC model\",\n      \"pmids\": [\"35126725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand/adaptor coupling in macrophages not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified transcriptional silencing of SLAMF6 in cancer, defining a TGF-\\u03b2/SMAD3/DNMT1 axis that hypermethylates the SLAMF6 promoter in CMS4 colorectal cancer.\",\n      \"evidence\": \"p-SMAD3 ChIP and EMSA on DNMT1 promoter, bisulfite/methylation-specific PCR, and in vivo 5-Aza treatment\",\n      \"pmids\": [\"41044679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SLAMF6 silencing on anti-tumor immunity not directly tested here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SLAMF6 in cytotoxic synapse organization, showing blockade impairs actin ring formation and CD8-CD4 conjugates needed for HIV-specific CTL killing.\",\n      \"evidence\": \"Anti-SLAMF6 blocking antibody, confocal imaging of actin rings, and CTL killing assays (preprint)\",\n      \"pmids\": [\"39896504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Molecular link between SLAMF6 and actin machinery not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competition between SAP/EAT-2 and SHP-1 at SLAMF6 ITSMs is quantitatively set in each cell type and engagement geometry (cis vs trans), and how this can be therapeutically biased toward activation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of adaptor competition across cell types\", \"Structural distinction between cis and trans engagement interfaces incomplete\", \"Endogenous control of isoform ratios in disease undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 9, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 13, 30]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 18, 33]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 13, 21, 29]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [8, 23, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 17, 18, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 15, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLAMF6\", \"SH2D1A\", \"SH2D1B\", \"FYN\", \"LCK\", \"PTPN6\", \"CD3Z\", \"VAV1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}