| 2001 |
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. |
Molecular cloning, tyrosine phosphorylation assays, co-immunoprecipitation with SAP and SHPs, functional NK cytotoxicity assays in XLP patient cells, antibody masking experiments |
The Journal of experimental medicine |
High |
11489943
|
| 2004 |
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. |
Chimeric Fc-fusion protein binding assay, ELISA, plasmon resonance, surface expression downregulation assay, NK cytotoxicity assay |
European journal of immunology |
High |
15162436
|
| 2004 |
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. |
Trimeric recombinant protein binding assay, NK cytotoxicity assay, proliferation assay, cytokine secretion assay |
Journal of immunology (Baltimore, Md. : 1950) |
High |
15153464
|
| 2004 |
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. |
Antibody cross-linking, phosphorylation assay, co-immunoprecipitation with SAP, cytokine ELISA, T cell differentiation assays, in vivo EAE model with NTB-A-Fc treatment |
The Journal of biological chemistry |
Medium |
14988414
|
| 2005 |
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. |
Targeted gene disruption (knockout mice), in vitro cytokine assays, in vivo Leishmania infection model, Salmonella infection model, ROS production assay |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
15879084
|
| 2006 |
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. |
X-ray crystallography at 3.0 Å resolution, analytical ultracentrifugation |
Immunity |
High |
17045824
|
| 2006 |
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. |
NTB-A tyrosine mutant expression in NTB-A-negative NK cell line, SAP knockdown by siRNA, functional cytotoxicity and cytokine assays, co-immunoprecipitation |
Journal of immunology (Baltimore, Md. : 1950) |
High |
16920955
|
| 2006 |
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. |
Allele-specific expression analysis, B cell tolerance assays (anergy, deletion, receptor revision) in congenic mouse strains |
Science (New York, N.Y.) |
Medium |
16778059
|
| 2007 |
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. |
Genetic mouse models (Slamf6 knockout, SAP knockout, Fyn knockout), thymocyte co-culture assays, NKT cell developmental analysis by flow cytometry |
Immunity |
High |
18031695
|
| 2008 |
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. |
Tyrosine phosphorylation assays, co-immunoprecipitation, analysis of SAP-FynT pathway mutant T cells, isoform comparison |
The Journal of biological chemistry |
High |
18482989
|
| 2010 |
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. |
Co-immunoprecipitation of Vpu with NTB-A, flow cytometry of surface NTB-A, NK degranulation assays, Vpu mutant virus comparison |
Cell host & microbe |
High |
21075351
|
| 2011 |
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. |
Antibody co-stimulation assays, intracellular cytokine staining, correlation with disease activity, SAP requirement established by comparison with XLP patients |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
22184727
|
| 2011 |
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. |
Transgenic mouse overexpression, autoantibody assays, in vivo lupus model (B6.Sle1b congenic) |
The Journal of experimental medicine |
Medium |
21422172
|
| 2012 |
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. |
Genetic epistasis (Slamf6-/-/Sh2d1a-/- double knockout mice), germinal center analysis, NKT cell developmental assays, ITSM mutagenesis, SHP-1 recruitment assays |
Immunity |
High |
22683125
|
| 2012 |
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. |
Tyrosine phosphorylation analysis of thymic lysates, disaggregation kinetics, isoform-specific expression analysis, comparison of SAP-null and Fyn-null mice |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
22393150
|
| 2013 |
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. |
Thymocyte co-stimulation assays, ChIP assay (Egr-2 binding to Zbtb16 promoter), flow cytometry, Ly108-deficient mouse analysis |
Journal of immunology (Baltimore, Md. : 1950) |
High |
23355739
|
| 2013 |
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. |
Glycosylation analysis (EndoH/PNGaseF digestion), immunofluorescence/confocal microscopy for Golgi retention, comparison of multiple Vpu variants |
Virology |
Medium |
23528733
|
| 2014 |
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. |
Co-immunoprecipitation of LCK with NTB-A, LCK kinase activity assay, RICD assay, ITSM requirement analysis, SAP siRNA knockdown, XLP patient T cells |
Journal of immunology (Baltimore, Md. : 1950) |
High |
24688028
|
| 2014 |
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. |
FRET/imaging within 100-200 nm, transmembrane domain replacement mutants, CD3ζ phosphorylation assay, T cell-APC adhesion assay, SHP-1 co-immunoprecipitation |
Journal of immunology (Baltimore, Md. : 1950) |
High |
25217164
|
| 2015 |
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. |
Triple knockout mice, T-independent and T-dependent antibody assays, adoptive co-transfer experiments, anti-SLAMF6 mAb treatment |
Frontiers in immunology |
Medium |
25926831
|
| 2015 |
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. |
Reporter-based bacterial binding assay, Slamf6-/- Rag-/- mouse infection model, anti-Slamf6 mAb blocking of bacterial interactions, cytokine analysis |
International immunology |
Medium |
25957267
|
| 2016 |
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. |
SLAMF6 knockout mice, SAP adaptor knockout mice, NK cell education assays, hematopoietic chimera experiments |
Nature immunology |
High |
26878112
|
| 2016 |
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. |
Adoptive transfer of KO T cells, flow cytometry for Tfh/GC B cells, autoantibody ELISA, double KO epistasis |
Clinical immunology (Orlando, Fla.) |
Medium |
27368806
|
| 2017 |
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. |
Co-culture of naive B and T cells, antibody blocking of SLAMF6, cytokine/receptor expression analysis, XLP patient cells, SAP-null comparison |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
28904129
|
| 2012 |
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. |
ChIP assay for NFAT1 and RORγt binding to IL17A promoter, nuclear fractionation, co-stimulation assays |
The Journal of biological chemistry |
Medium |
22989874
|
| 2013 |
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. |
SAP knockdown in primary NK cells, raft recruitment analysis, phosphorylation assay, EAT-2 knockdown, cytotoxicity assay |
Frontiers in immunology |
Medium |
23346089
|
| 2016 |
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. |
CRISPR/Cas9 triple gene knockout, iNKT cell developmental analysis by flow cytometry, germinal center analysis post-immunization |
PloS one |
Medium |
27258160
|
| 2016 |
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. |
Direct binding assays between recombinant receptors and HA, sialylation dependency experiments, NA treatment, NK cytotoxicity assays |
Oncotarget |
Medium |
26919106
|
| 2019 |
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. |
Biochemical and genetic experiments (SLAMF6 domain mutants), flow cytometry, live-cell imaging, Rap1 activation assay, T cell adhesion assay |
PloS one |
Medium |
31199820
|
| 2020 |
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. |
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 |
eLife |
High |
32122464
|
| 2021 |
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. |
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 |
Cancer immunology research |
High |
33762352
|
| 2022 |
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. |
Co-immunoprecipitation of SLAMF6 with TCR signaling proteins, bispecific antibody engineering, T cell activation assays, co-culture assays |
Life science alliance |
Medium |
36622343
|
| 2022 |
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. |
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 |
Oncology letters |
Medium |
35126725
|
| 2025 |
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. |
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 |
Nature |
High |
41673151
|
| 2025 |
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. |
SLAMF6 knockout in AML cells, T cell co-culture cytotoxicity assays, anti-SLAMF6 dimerization site antibody, humanized in vivo AML models |
Nature cancer |
High |
41044242
|
| 2025 |
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. |
Anti-SLAMF6 blocking antibody, CTL-target cell conjugate assays, confocal microscopy of actin ring formation, killing efficiency assays using CTL lines from HIV+ patients |
bioRxivpreprint |
Medium |
39896504
|
| 2017 |
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. |
siRNA knockdown of Ly108 on dendritic cells, peptide-blocking of Ly108, iNKT cell activation assays (cytokine production), human iNKT validation |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
28373584
|
| 2025 |
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. |
Strain comparison (BALB/c vs B6), SLAMF6 expression quantification by flow cytometry, basal TCR signaling measurement in preselected DP thymocytes, iNKT subset analysis |
International immunology |
Low |
40405353
|
| 2025 |
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. |
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 |
Clinical epigenetics |
Medium |
41044679
|