Affinage

SLAMF6

SLAM family member 6 · UniProt Q96DU3

Length
332 aa
Mass
37.3 kDa
Annotated
2026-04-28
84 papers in source corpus 39 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLAMF6 (NTB-A/Ly108) is a homophilic immunoglobulin superfamily receptor that functions as a molecular switch in NK cells, T cells, B cells, and myeloid cells, toggling between activating and inhibitory signaling depending on the availability of the adaptor SAP (SH2D1A) versus the phosphatase SHP-1. The receptor engages in both trans (cell–cell) and cis (same-cell) homophilic interactions through an end-to-end ectodomain dimer interface; trans engagement at the immunological synapse co-stimulates TCR signaling, promotes Rap1-dependent adhesion, and drives NKT cell lineage development and Tfh–GC B cell interactions via SAP/Fyn-dependent recruitment of Vav-1, c-Cbl, and LCK, whereas cis interactions on T cells are constitutively inhibitory and limit anti-tumor immunity (PMID:11489943, PMID:17045824, PMID:18031695, PMID:22683125, PMID:31199820, PMID:41673151). When SAP is absent (as in X-linked lymphoproliferative disease), SHP-1 occupies the cytoplasmic ITSMs, converting SLAMF6 into an inhibitory receptor that dampens CD3ζ phosphorylation, T–B adhesion, and germinal center responses; SAP and SHP-1 thus compete at the ITSMs to set a signaling rheostat controlling humoral immunity, B cell tolerance, and autoimmunity (PMID:22683125, PMID:25217164, PMID:16778059). Alternative splicing further tunes function: the short SLAMF6Δ17-65 isoform is agonistic and drives a TBX21/RUNX3 cytotoxic program that enhances anti-tumor TIL activity, while the Ly108-H1 isoform acts as an immune-suppressive decoy that restrains lupus-like autoimmunity (PMID:33762352, PMID:21422172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2001 High

    Identification of NTB-A as an NK-cell receptor whose signaling output—activating or inhibitory—depends on the presence of SAP resolved why XLP patients have defective NK cytotoxicity and established SLAMF6 as a SAP-dependent signaling switch.

    Evidence Molecular cloning, co-immunoprecipitation of SAP and SHPs, functional NK cytotoxicity assays with XLP patient cells

    PMID:11489943

    Open questions at the time
    • Downstream effectors beyond SAP/SHP association not yet defined
    • Ligand identity unknown at this point
  2. 2004 High

    Demonstration that SLAMF6 is its own ligand and co-stimulates T cell proliferation, Th1 differentiation, and B cell isotype switching established the receptor as a homophilic co-stimulatory molecule operating in both innate and adaptive immunity.

    Evidence Recombinant trimeric NTB-A fusion proteins for homophilic binding (SPR, ELISA), T cell co-stimulation assays, in vivo EAE blockade with soluble NTB-A-Fc

    PMID:14988414 PMID:15153464 PMID:15162436

    Open questions at the time
    • Structural basis of homophilic interaction unresolved
    • Relative contribution to T versus NK biology unclear
  3. 2005 High

    Ly108 knockout mice revealed an unexpected non-lymphocyte role: SLAMF6 controls neutrophil bactericidal ROS production and host defense against Salmonella, broadening the receptor's functional scope beyond NK and T cells.

    Evidence Targeted Ly108 disruption in mice, in vitro and in vivo Salmonella infection, ROS measurement

    PMID:15879084

    Open questions at the time
    • Mechanism linking SLAMF6 to NADPH oxidase activation not defined
    • Whether SAP adaptors mediate the neutrophil phenotype unknown
  4. 2006 High

    The crystal structure of the NTB-A ectodomain at 3.0 Å revealed a rod-like monomer self-associating into a kinked dimer, providing the molecular basis for homophilic specificity within the SLAM family, while mutagenesis of cytoplasmic ITSMs and adaptor knockdown dissected differential EAT-2 (cytotoxicity) versus SAP (IFN-γ) requirements and identified the lupus-associated Ly108.1 allele as a regulator of B cell tolerance checkpoints.

    Evidence X-ray crystallography; reconstitution of NTB-A tail mutants in NK cells with SAP/EAT-2 knockdown; genetic analysis of congenic lupus-prone mouse strains with B cell tolerance assays

    PMID:16778059 PMID:16920955 PMID:17045824

    Open questions at the time
    • Structural determinants of adaptor selectivity at ITSM not resolved at atomic level
    • How allelic variants differentially engage downstream signaling in B cells mechanistically unclear
  5. 2007 High

    Genetic epistasis in Slamf6/Slamf1 double-KO, SAP-KO, and Fyn-KO mice established that SLAMF6 homophilic engagement during thymocyte–thymocyte interactions provides SAP/Fyn-dependent co-stimulation essential for NKT cell lineage commitment.

    Evidence Single and compound gene knockouts with NKT cell developmental analysis in thymus

    PMID:18031695

    Open questions at the time
    • Whether SLAMF6 acts at selection or expansion stage of NKT development not resolved
    • Transcription factor targets downstream of SAP/Fyn in NKT lineage unknown
  6. 2008 High

    Signaling biochemistry downstream of Ly108 was mapped: SAP- and Fyn-dependent phosphorylation of Vav-1 and c-Cbl, with the lupus-associated Ly108-1 isoform triggering stronger signaling due to an additional cytoplasmic tyrosine, providing a molecular explanation for allelic autoimmune susceptibility.

    Evidence Phosphorylation assays and co-IP in T cells from SAP-KO and Fyn-mutant mice, isoform comparison

    PMID:18482989

    Open questions at the time
    • Quantitative contribution of Vav-1 versus c-Cbl to downstream phenotypes unknown
    • Isoform-specific interactomes not comprehensively mapped
  7. 2010 High

    HIV-1 Vpu was shown to retain NTB-A in the Golgi by preventing glycosylation maturation, thereby shielding infected cells from NK-mediated killing, establishing SLAMF6 as a target of viral immune evasion.

    Evidence Vpu mutant virus infection, glycosylation analysis, NK degranulation assays, co-IP of Vpu–NTB-A

    PMID:21075351 PMID:23528733

    Open questions at the time
    • Precise Vpu–NTB-A binding interface unknown
    • Whether other SLAM family members are similarly targeted not addressed
  8. 2011 High

    Discovery that the Ly108-H1 isoform suppresses autoimmunity when transgenically expressed in lupus-prone mice, and that SLAMF6 co-stimulation promotes IL-17 production via RORγt and NFAT1 recruitment to the IL17A promoter, revealed isoform-specific and SAP-dependent control of T helper differentiation pathways.

    Evidence Transgenic Ly108-H1 mice in B6.Sle1b background; ChIP for RORγt and NFAT1 at IL17A promoter; SAP-deficient controls

    PMID:21422172 PMID:22184727 PMID:22989874

    Open questions at the time
    • How Ly108-H1 mechanistically suppresses signaling (decoy versus active inhibition) unclear
    • Whether SLAMF6-driven Th17 effect is cell-autonomous not fully resolved
  9. 2012 High

    The SAP-SHP-1 rheostat model was established: deletion of Ly108 in SAP-deficient mice rescued germinal center responses by removing the SHP-1-recruiting inhibitory signal, proving that SLAMF6 ITSMs serve as a competitive binding platform where SAP and SHP-1 antagonize each other to regulate T cell help to B cells.

    Evidence Slamf6−/− × Sh2d1a−/− double-KO epistasis, SHP-1 recruitment imaging at immunological synapse, ITSM mutant analysis

    PMID:22683125

    Open questions at the time
    • Quantitative kinetics of SAP versus SHP-1 competition at the ITSM not measured
    • Whether phosphatase SHP-2 also participates in this rheostat not tested
  10. 2013 High

    SLAMF6 was linked to transcriptional programming of innate-like T cells: co-stimulation of preselection thymocytes enhanced PLZF expression through Egr-2 binding to the Zbtb16 promoter, while SAP was shown to be required upstream of EAT-2 recruitment to NTB-A for NK cytotoxicity, defining an adaptor hierarchy.

    Evidence ChIP for Egr-2 at Zbtb16 promoter, Ly108-KO thymocyte analysis; SAP knockdown in NK cells with EAT-2 recruitment assays

    PMID:22393150 PMID:23346089 PMID:23355739

    Open questions at the time
    • Whether Egr-2–PLZF axis is exclusive to Ly108 or shared with other SLAM receptors unknown
    • How phosphorylation-incompetent Ly108-H1 exerts its effects in thymus not defined
  11. 2014 High

    Two mechanistic refinements emerged: SAP recruits LCK (not Fyn) to NTB-A in activated human T cells to amplify proximal TCR signaling and promote restimulation-induced cell death, and Ly108 dampens T–B adhesion through a two-level CD3ζ dephosphorylation mechanism involving constitutive SHP-1 colocalization and ligation-dependent transmembrane domain interaction.

    Evidence Co-IP and kinase activity assays with XLP patient T cells; Ly108 transmembrane swap mutants with T–B conjugation assays

    PMID:24688028 PMID:25217164

    Open questions at the time
    • Whether LCK recruitment occurs in all T cell subsets or only restimulated cells unclear
    • Structural basis of transmembrane domain-mediated Ly108–CD3ζ interaction unresolved
  12. 2015 High

    SLAMF6 was established as a negative regulator of humoral immunity: anti-SLAMF6 mAb treatment inhibited Tfh and GC B cell development, and B cell-intrinsic Ly108 expression modulated GC tolerance, BCR signaling strength, and autoantibody production.

    Evidence Single and triple SLAM KO mice, adoptive transfer, anti-SLAMF6 mAb in vivo; BAC-transgenic Ly108 overexpression with GC and BCR signaling analysis

    PMID:25801429 PMID:25926831

    Open questions at the time
    • Whether SLAMF6 inhibits Tfh through cis or trans interactions not distinguished
    • Downstream phosphatase versus adaptor usage in GC B cells not defined
  13. 2016 High

    Multiple studies converged to show SLAMF6 tunes NK education (SAP uncouples SLAMF6 from SHP-1 to allow NK responsiveness toward non-hematopoietic targets), cooperates with SLAMF1 to restrain autoimmunity, and worsens iNKT developmental defects when deleted in combination with other SLAM receptors.

    Evidence SLAMF6-KO and SAP-KO NK assays against hematopoietic and non-hematopoietic targets; Slamf6-KO T cell adoptive transfer autoimmunity; CRISPR triple-KO iNKT analysis

    PMID:26878112 PMID:26919106 PMID:27258160 PMID:27368806

    Open questions at the time
    • Molecular basis of NK 'education' by SLAMF6–SHP-1 not fully elucidated
    • Whether SLAMF6 binding to influenza HA has physiological relevance in vivo unclear
  14. 2017 High

    SLAMF6 homophilic trans interactions between T and B cells were shown to induce cell-type-specific downstream programs—MIF secretion in T cells and CD74 upregulation in B cells promoting B cell survival—and SLAMF6 trans engagement on dendritic cells was required for optimal iNKT cell activation.

    Evidence T–B cell interaction assays with XLP patient cells; siRNA and peptide-blocking of Ly108 in DC–iNKT co-cultures

    PMID:28373584 PMID:28904129

    Open questions at the time
    • Whether MIF–CD74 axis is the primary B cell survival pathway downstream of SLAMF6 not confirmed by genetic rescue
    • Signaling cascade linking Ly108 engagement on DCs to iNKT activation not mapped
  15. 2018 High

    A soluble SLAMF6 ectodomain was shown to enhance TIL function by reducing activation-induced cell death and accelerating SLAMF6 dephosphorylation, providing the first therapeutic proof-of-concept for modulating SLAMF6 signaling to boost anti-tumor immunity.

    Evidence Recombinant ectodomain protein, AICD and phosphorylation assays, in vivo adoptive transfer tumor model

    PMID:29305520

    Open questions at the time
    • Whether soluble ectodomain disrupts cis or trans interactions selectively not determined
    • Pharmacokinetics and target engagement in vivo not characterized
  16. 2019 High

    SLAMF6 clustering with the TCR at the immunological synapse was shown to amplify downstream signaling through Rap1 GTPase activation, with tyrosine 308 in the cytoplasmic tail critical for this effect, providing a spatial mechanism for SLAMF6 co-stimulation.

    Evidence Biochemical clustering and Rap1 activation assays, cytoplasmic tail Y308 mutants, synapse imaging

    PMID:31199820

    Open questions at the time
    • GEF linking SLAMF6 to Rap1 activation not identified
    • Whether Y308-dependent signaling is SAP-dependent or independent not tested
  17. 2020 High

    SLAMF6 deletion in CD8+ T cells skewed toward a T-bet-dominant effector phenotype with enhanced polyfunctionality and lasting tumor regression, identifying SLAMF6 as an inhibitory checkpoint whose absence improves adoptive cell therapy; LAG-3 upregulation was identified as a compensatory mechanism.

    Evidence SLAMF6−/− × Pmel-1 TCR transgenic mice, adoptive transfer melanoma model, transcription factor and cytolysis analysis

    PMID:32122464

    Open questions at the time
    • Whether the effector skewing is due to loss of cis or trans SLAMF6 engagement not determined at this time
    • Interaction between SLAMF6 and other checkpoint receptors beyond LAG-3 not explored
  18. 2021 High

    Isoform-level dissection revealed that canonical SLAMF6 is inhibitory through SAP, while the SLAMF6Δ17-65 splice variant is agonistic through SHP-1 and drives a TBX21/RUNX3 cytotoxic program; splice-switching antisense oligonucleotides promoting this isoform improved anti-tumor TIL function, opening a new therapeutic modality.

    Evidence Isoform functional assays, SAP and SHP-1 dependency analysis, ASO-mediated splice switching in TILs, in vivo tumor model

    PMID:33762352

    Open questions at the time
    • Crystal structure of SLAMF6Δ17-65 ectodomain and how deletion alters homophilic binding unknown
    • Whether the short isoform engages in cis or only trans interactions not tested
  19. 2022 High

    Bispecific antibody studies confirmed that SLAMF6 physical proximity to the CD3 complex is functionally important—forcing co-clustering enhanced T cell activation—while a separate study showed SLAMF6 promotes macrophage M2 polarization in hepatocellular carcinoma through NF-κB, extending SLAMF6 function into tumor-associated macrophage biology.

    Evidence Co-IP and bispecific antibody functional assays for TCR co-clustering; Ly108 siRNA in macrophages with NF-κB pathway and HCC co-culture assays

    PMID:35126725 PMID:36622343

    Open questions at the time
    • Stoichiometry of SLAMF6–CD3 complex association not quantified
    • Whether SLAMF6-driven M2 polarization depends on SAP or SHP-1 not determined
  20. 2025 High

    The paradigm-shifting discovery that SLAMF6 engages in cis homophilic interactions on the T cell surface that are constitutively inhibitory—independently of tumor-expressed SLAMF6—and that disrupting these cis interactions with antibodies potently enhances anti-tumor immunity, while separately SLAMF6 expression on AML blasts was shown to mediate immune evasion reversible by dimerization-blocking antibodies, established SLAMF6 as a next-generation immune checkpoint target.

    Evidence Cis interaction assays, cis-blocking versus trans-blocking antibodies in vitro and in vivo tumor models; CRISPR KO of SLAMF6 in AML cells with dimerization-blocking antibody in humanized models; strain comparison of SLAMF6 expression and basal TCR signaling in thymocytes

    PMID:40405353 PMID:41044242 PMID:41673151

    Open questions at the time
    • Structural basis distinguishing cis from trans homophilic interfaces not resolved
    • Whether cis-blocking antibodies affect normal immune homeostasis long-term unknown
    • Biomarkers predicting patient response to SLAMF6-targeted therapy not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural distinction between cis and trans SLAMF6 dimer interfaces, the quantitative competition kinetics of SAP versus SHP-1 at ITSMs in different immune cell subsets, the mechanism by which SLAMF6 activates neutrophil NADPH oxidase, and whether therapeutic targeting of SLAMF6 (blocking antibodies, splice-switching oligonucleotides) can achieve selective modulation without disrupting immune homeostasis.
  • Atomic-resolution structure of cis dimer versus trans dimer not available
  • SAP/SHP-1 competition kinetics not measured quantitatively in any cell type
  • Mechanism linking SLAMF6 to neutrophil ROS production undefined
  • In vivo therapeutic window for SLAMF6-targeting agents not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 8 GO:0098772 molecular function regulator activity 5 GO:0098631 cell adhesion mediator activity 4
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-168256 Immune System 12 R-HSA-1500931 Cell-Cell communication 7 R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4
Partners
CBLFYNLCKPTPN6SH2D1ASH2D1BVAV1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NTB-A (SLAMF6) undergoes tyrosine phosphorylation 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, Co-immunoprecipitation, functional NK cell cytotoxicity assays with patient cells and mAb-masking experiments The Journal of experimental medicine High 11489943
2004 NTB-A (SLAMF6) is its own ligand, engaging in homophilic interaction; this homophilic binding activates NK cell cytotoxicity, influences NK cell proliferation, and stimulates IFN-γ secretion. Recombinant trimeric NTB-A fusion proteins used as probes; functional NK cytotoxicity, proliferation, and cytokine assays; surface plasmon resonance and ELISA confirming homophilic binding European journal of immunology / Journal of immunology High 15153464 15162436
2004 Cross-linking of NTB-A (SLAMF6) induces tyrosine phosphorylation of the receptor and recruitment of SAP; NTB-A co-stimulation with CD3 drives T cell proliferation, IFN-γ secretion, and Th1 differentiation; soluble NTB-A-Fc fusion protein blocks B cell isotype switching and delays experimental autoimmune encephalomyelitis in vivo. mAb cross-linking, phosphorylation assays, Co-IP, T cell differentiation assays, in vivo EAE model with soluble fusion protein blockade The Journal of biological chemistry High 14988414
2006 Crystal structure of the NTB-A (SLAMF6) ectodomain solved at 3.0 Å reveals a rod-like monomer that self-associates into a highly kinked dimer via end-to-end homophilic interaction; structural comparison with CD2-CD58 identifies the molecular basis for binding specificity within the SLAM family. X-ray crystallography at 3.0 Å resolution Immunity High 17045824
2006 NTB-A (SLAMF6) is constitutively tyrosine phosphorylated in unstimulated NK cells by Src family kinases, likely due to homophilic NK-NK interactions; the second ITSM tyrosine (Y2) is essential for NTB-A-mediated cytotoxicity; EAT-2 (not SAP) is recruited to Y2 and is required for cytotoxicity, while SAP (not EAT-2) is required for NTB-A-mediated IFN-γ production, revealing differential adapter requirements for cytotoxicity vs. cytokine release. NTB-A-negative NK cell line reconstituted with cytoplasmic tail mutants; SAP knockdown; EAT-2 knockdown; cytotoxicity and IFN-γ production assays Journal of immunology High 16920955
2006 The Ly108.2 allele (normal), but not the lupus-associated Ly108.1 allele, sensitizes immature B cells to deletion and RAG re-expression, establishing Ly108 (SLAMF6) as a regulator of B cell tolerance checkpoints. Genetic analysis of congenic mouse strains, B cell functional assays (anergy, deletion, receptor revision) Science High 16778059
2007 Homophilic engagement of Slamf6 (Ly108) and Slamf1 on cortical thymocytes generates 'second signals' requiring SAP recruitment and Fyn kinase activation; these signals are essential for NKT cell lineage development and only occur during T-T (not T-stromal cell) interactions because stromal cells do not express Slamf6 or Slamf1. Targeted gene disruption (Slamf6 and Slamf1 knockout mice), genetic epistasis with SAP and Fyn mutants, NKT cell developmental assays Immunity High 18031695
2005 Ly108 (SLAMF6) controls neutrophil bactericidal activity: Ly108-deficient neutrophils have severely reduced reactive oxygen species production after bacterial phagocytosis and increased susceptibility to Salmonella typhimurium infection; Ly108 also regulates CD4+ T cell IL-4 production. Targeted disruption of Ly108 exons 2 and 3 in mice; in vitro and in vivo Salmonella infection assays; ROS measurement; cytokine assays Journal of immunology High 15879084
2008 Ly108 (SLAMF6) mediates tyrosine phosphorylation signaling involving Vav-1 and c-Cbl in a manner strictly dependent on SAP expression and Fyn kinase; the lupus-associated Ly108-1 isoform triggers stronger tyrosine phosphorylation than Ly108-2 due to an additional unique intra-cytoplasmic tyrosine-based motif. In vitro phosphorylation assays, co-immunoprecipitation, comparison of T cells from SAP-deficient and FynT-mutant mice, isoform-specific signaling analysis The Journal of biological chemistry High 18482989
2010 HIV-1 Vpu downmodulates NTB-A (SLAMF6) surface expression on infected CD4+ T cells through its transmembrane region, retaining NTB-A within the Golgi by affecting glycosylation (only high-mannose form detectable), thereby preventing NK cell degranulation and protecting infected cells from NK-mediated lysis. Vpu mutant virus infection assays, NK cell degranulation assays, glycosylation analysis, co-immunoprecipitation of Vpu-NTB-A association Cell host & microbe / Virology High 21075351 23528733
2012 Deletion of Ly108 (Slamf6) in SAP-deficient CD4+ T cells reverses the germinal center defect of Sh2d1a-/- mice; Ly108 negative signaling requires ITSMs and SHP-1 recruitment, generating high amounts of SHP-1 at the T cell:B cell synapse and limiting T:B adhesion; SAP and SHP-1 compete for Ly108 ITSM binding to act as a rheostat for T cell help. Genetic epistasis (Slamf6-/- crossed to Sh2d1a-/-), germinal center assays, SHP-1 recruitment assays at immunological synapse, ITSM mutant analysis Immunity High 22683125
2013 Ly108 (SLAMF6) is constitutively tyrosine phosphorylated in murine thymus in a SAP- and Fyn kinase-dependent manner; phosphorylation is rapidly lost after thymocyte disaggregation indicating dynamic contact-mediated regulation; the Ly108-H1 isoform does not undergo tyrosine phosphorylation, suggesting it functions as a decoy isoform. Thymocyte phosphorylation assays, SAP and Fyn KO comparisons, isoform-specific phosphorylation analysis Journal of immunology High 22393150
2013 Ly108 (SLAMF6) co-stimulation of preselection double-positive thymocytes markedly enhances PLZF transcription factor expression compared to TCR stimulation alone; this occurs through increased Egr-2 expression and Egr-2 binding to the Zbtb16 (PLZF) promoter; Ly108-deficient mice have decreased PLZF-expressing CD4+ T cells. Chromatin immunoprecipitation (Egr-2 at Zbtb16 promoter), flow cytometry, Ly108 KO mouse analysis, co-stimulation assays Journal of immunology High 23355739
2014 SAP facilitates recruitment and activation of LCK (but not FYN) at NTB-A (SLAMF6) receptors in activated human T cells upon TCR restimulation; both ITSMs are required; NTB-A-associated LCK phosphorylation and kinase activity amplify proximal TCR signaling to promote restimulation-induced cell death (RICD); this is abrogated in XLP (SAP-deficient) T cells. Co-immunoprecipitation, kinase activity assays, SAP siRNA knockdown, comparison with XLP patient T cells, RICD assays Journal of immunology High 24688028
2014 Ly108 (SLAMF6) dampens T cell adhesion to B cells and dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108-CD3ζ interaction: (1) constitutive colocalization-dependent inhibition via SHP-1 associated with Ly108, and (2) ligation-dependent Ly108-CD3ζ interaction requiring the Ly108 transmembrane domain, leading to more efficient CD3ζ dephosphorylation. Co-immunoprecipitation of Ly108-CD3ζ, transmembrane domain swap mutants, proximity assays, T-B conjugation assays, phosphorylation measurements Journal of immunology High 25217164
2015 SLAMF6 deletion combined with SLAMF1 and SLAMF5 deletion results in enhanced T-dependent and T-independent antibody responses; both B and T cells from triple knockout mice contribute to enhanced responses; anti-SLAMF6 mAb treatment inhibits Tfh cell and GC B cell development, establishing SLAMF6 as a negative regulator of humoral immunity. Single and triple gene KO mice, adoptive co-transfer assays, anti-SLAMF6 mAb treatment, GC and Tfh cell analysis Frontiers in immunology High 25926831
2016 SLAMF6 on NK cells enhances NK cell activation against nonhematopoietic target cells (which lack SLAM ligands) through a mechanism regulated by SAP adaptors; SAP uncouples SLAMF6 from SHP-1, reducing the negative effect of SLAMF6 on NK responsiveness toward nonhematopoietic targets, defining a SLAM-SAP pathway that influences NK cell 'education'. SLAMF6 and SAP family knockout mice, NK cell activation assays against hematopoietic and nonhematopoietic targets, phosphatase association analysis Nature immunology High 26878112
2016 Transfer of Slamf6-/- CD4+ T cells induces SLE-like autoimmunity with elevated autoantibodies, Tfh cells, and GC B cells; the Slamf6-H1 isoform expressed in Slamf6-/- T cells does not cause this phenotype; Slamf1 is required for the pro-autoimmune effect of Slamf6 deficiency, placing SLAMF6 as an inhibitory receptor that controls autoimmune responses in cooperation with SLAMF1. Adoptive transfer of KO T cells into bm12 recipients, multi-receptor KO epistasis analysis, autoantibody measurement, Tfh/GC analysis Clinical immunology High 27368806
2011 SLAMF3 and SLAMF6 co-engagement with CD3 under Th17 polarizing conditions increases IL-17 production in a SAP-dependent manner; SLAM co-stimulation promotes RORγt recruitment to the IL17A promoter and increases nuclear NFAT1 occupancy; SLAMF6-driven IL-17 production is severely defective in SLE T cells. mAb co-stimulation assays, SAP-deficient controls, chromatin immunoprecipitation (RORγt and NFAT1 at IL17A promoter), cytokine ELISAs Journal of immunology / The Journal of biological chemistry High 22184727 22989874
2017 SLAMF6 homophilic interactions between naive T and B cells induce cell type-specific signals mediated by SAP adaptors, leading to upregulation of migration inhibitory factor (MIF) in T cells and augmented CD74 expression on B cells, consequently enhancing B cell survival; SAP deficiency in XLP patients reduces CD74 expression and perturbs naive B cell maintenance. Cell-cell interaction assays, SAP-deficient patient analysis, cytokine and receptor expression measurements, XLP patient B cell survival assays Journal of immunology High 28904129
2017 Trans Ly108 (SLAMF6) interactions between dendritic cells and iNKT cells are critical for robust iNKT cell activation; siRNA knockdown and peptide-blocking strategies specifically abrogated trans-Ly108-mediated co-stimulation; Ly108 co-stimulation similarly enhanced human iNKT cell activation. siRNA knockdown, peptide-blocking, functional iNKT activation assays in mice and human cells Journal of immunology High 28373584
2019 SLAMF6 clustering specifically with TCR at the immunological synapse dramatically increases downstream TCR signaling; tyrosine 308 in the SLAMF6 cytoplasmic tail is crucial for T cell function enhancement; the SLAMF6 ectodomain is required for function but not for synapse recruitment; SLAMF6 enhances T cell adhesiveness through activation of the small GTPase Rap1. Biochemical clustering assays, cytoplasmic tail tyrosine mutants, imaging studies of synapse localization, Rap1 activation assays, genetic SLAMF6 deletion PloS one High 31199820
2013 NK cytotoxicity mediated by NTB-A (SLAMF6) via 2B4 is dependent on SAP acting downstream of receptor phosphorylation; SAP knockdown does not affect lipid raft recruitment or receptor phosphorylation, but abrogates EAT-2 recruitment to NTB-A, revealing novel cooperativity between SAP and EAT-2 adaptors. SAP knockdown in primary human NK cells, raft fractionation, phosphorylation assays, EAT-2 recruitment assays, cytotoxicity assays Frontiers in immunology High 23346089
2021 The canonical SLAMF6 isoform inhibits T cell activation through SAP recruitment, while the short splice isoform SLAMF6Δ17-65 has a strong agonistic effect dependent on SHP-1; the costimulatory action of SLAMF6Δ17-65 leads to a cytotoxic molecular profile mediated by TBX21 and RUNX3 expression; splice-switching antisense oligonucleotides promoting SLAMF6Δ17-65 improved tumor-infiltrating lymphocyte anti-tumor function. Isoform expression, SAP and SHP-1 functional assays, transcription factor expression profiling, ASO-mediated splice switching, in vivo tumor model Cancer immunology research High 33762352
2022 SLAMF6 co-localization with the CD3 complex enhances T cell activity; co-immunoprecipitation revealed SLAMF6 interacts with proteins essential for TCR downstream signaling; bispecific anti-CD3/SLAMF6 antibodies promoting SLAMF6-CD3 clustering enhanced T cell activation, while anti-CD45/SLAMF6 antibodies inhibiting SLAMF6-TCR clustering also enhanced activation through steric hindrance. Co-immunoprecipitation, biochemical colocalization assays, bispecific antibody functional studies, co-culture assays Life science alliance High 36622343
2016 CRISPR-mediated triple knockout of SLAMF1, SLAMF5, and SLAMF6 worsens iNKT cell development defects seen in SLAMF6 single knockouts, supporting positive signaling roles for these receptors in iNKT development with potential redundancy; triple KO does not grossly affect conventional T or B cell development. Cas9/CRISPR triple gene disruption, flow cytometric analysis of lymphocyte development PloS one High 27258160
2022 SLAMF6/Ly108 promotes macrophage M2 polarization in hepatocellular carcinoma; Ly108 siRNA silencing in macrophages suppresses M2 polarization and attenuates HCC cell migration and invasion by inhibiting the NF-κB pathway; the tumor microenvironment upregulates Ly108 expression in macrophages. siRNA knockdown of Ly108 in macrophages, M2 polarization marker assays (RT-qPCR), NF-κB pathway analysis, clonogenic and Transwell assays, murine HCC model Oncology letters Medium 35126725
2016 NTB-A (SLAMF6) and 2B4 directly bind influenza hemagglutinin (HA) in a sialic acid-dependent manner and co-stimulate NK cell killing of influenza-infected cells; viral neuraminidase counteracts these interactions. Direct receptor-HA binding assays, sialylation-dependent binding identification, NK cytotoxicity assays, binding site mutagenesis Oncotarget High 26919106
2020 SLAMF6 absence in CD8+ T cells skews toward an effector phenotype with T-bet as the dominant transcription factor and acquisition of effector-memory phenotype; SLAMF6-/- Pmel-1 T cells show improved polyfunctionality, superior tumor cytolysis, and lasting tumor regression upon adoptive transfer; LAG-3 is upregulated in SLAMF6-/- cells and combined LAG-3 blockade further improves anti-tumor response. SLAMF6-/- x Pmel-1 TCR transgenic mice, adoptive transfer melanoma model, transcription factor analysis, cytolysis assays eLife High 32122464
2025 SLAMF6 is triggered in cis by homotypic interactions at the T cell surface; these cis interactions elicit inhibitory effects that suppress T cell activation and limit anti-tumor immunity independently of SLAMF6 expression on tumor cells; antibodies disrupting cis interactions strongly augment T cell activation and inhibit tumor growth in vivo. cis homotypic interaction assays, mAb blocking experiments, T cell activation assays, in vivo tumor models, comparison of cis vs. trans blocking antibodies Nature High 41673151
2025 Aberrant expression of SLAMF6 on primitive AML cells constitutes an immune evasion mechanism; SLAMF6 knockout in AML cells enables T cell activation and killing; an antibody targeting the SLAMF6 dimerization site inhibits SLAMF6-SLAMF6 homophilic interaction and restores T cell killing both in vitro and in humanized in vivo models. CRISPR KO of SLAMF6 in AML cells, T cell coculture cytotoxicity assays, dimerization-blocking antibody, humanized in vivo AML models Nature cancer High 41044242
2025 SLAMF6 blockade impairs actin ring formation at the immunological synapse between HIV-specific CTLs and HIV-infected CD4+ T cells, reducing CD8+-CD4+ T cell conjugate formation and killing efficiency of HIV-specific CTLs. Anti-SLAMF6 blocking antibody, conjugate formation assays, immunological synapse imaging (actin ring), CTL killing assays with PLWH-derived CTL lines bioRxivpreprint Medium 39896504
2025 SLAMF6 expression level on immature thymocytes affects basal TCR signaling in preselected double-positive thymocytes; low SLAMF6 expression (as in BALB/c mice) results in high basal TCR signaling, associated with iNKT2 cell expansion; this reveals SLAMF6 as a regulator of basal TCR signaling influencing iNKT lineage diversity. Strain comparison (BALB/c vs B6), SLAMF6 expression measurement, basal TCR signaling assays in preselected DP thymocytes, iNKT subset analysis International immunology Medium 40405353
2018 Soluble SLAMF6 ectodomain (seSLAMF6, 203 aa) reduces activation-induced cell death in tumor-infiltrating lymphocytes, enhances IFN-γ secretion and cytolytic activity of CD8+ T cells, and expedites the loss of phosphorylation on SLAMF6 following TCR triggering; systemic administration sustains adoptively transferred CD8+ T cells in vivo and induces tumor clearance. Recombinant ectodomain protein, AICD assays, cytokine ELISA, phosphorylation assays, in vivo adoptive transfer tumor model Cancer immunology research High 29305520
2011 A novel isoform, Ly108-H1, is absent in lupus-prone congenic mice but present in C57BL/6 mice; transgenic expression of Ly108-H1 in B6.Sle1b mice markedly diminishes T cell-dependent autoimmunity, establishing the H1 isoform as an immune-suppressing variant of Ly108. Transgenic mouse generation, autoantibody measurement, T cell-dependent autoimmunity assays in congenic lupus model The Journal of experimental medicine High 21422172
2015 B cell-intrinsic expression of lupus-associated CD84 and Ly108 (SLAMF6) in germinal center B cells is sufficient to break B cell tolerance and increase autoantibody production; B6.Sle1b B cells have reduced BCR signaling and lower frequency of B-T cell conjugates compared to B6 controls overexpressing B6 Ly108; Ly108 modulates B cell tolerance at the GC checkpoint. BAC-transgenic mice overexpressing B6 Ly108 and CD84, GC analysis, BCR signaling assays, B-T cell conjugate frequency, autoantibody measurement Journal of immunology High 25801429

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 287 18031695
2001 NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. The Journal of experimental medicine 256 11489943
2006 Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science (New York, N.Y.) 181 16778059
2010 Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu. Cell host & microbe 153 21075351
2012 The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity 133 22683125
2004 Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells. European journal of immunology 84 15162436
2004 Cadmium uptake and translocation in tumbleweed (Salsola kali), a potential Cd-hyperaccumulator desert plant species: ICP/OES and XAS studies. Chemosphere 76 15081756
2005 Cutting edge: the SLAM family receptor Ly108 controls T cell and neutrophil functions. Journal of immunology (Baltimore, Md. : 1950) 65 15879084
2004 Cutting edge: NTB-A activates NK cells via homophilic interaction. Journal of immunology (Baltimore, Md. : 1950) 63 15153464
2006 NTB-A receptor crystal structure: insights into homophilic interactions in the signaling lymphocytic activation molecule receptor family. Immunity 60 17045824
2011 Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. Journal of immunology (Baltimore, Md. : 1950) 59 22184727
2016 A hematopoietic cell-driven mechanism involving SLAMF6 receptor, SAP adaptors and SHP-1 phosphatase regulates NK cell education. Nature immunology 58 26878112
2008 Control of T lymphocyte signaling by Ly108, a signaling lymphocytic activation molecule family receptor implicated in autoimmunity. The Journal of biological chemistry 56 18482989
2004 NTB-A, a new activating receptor in T cells that regulates autoimmune disease. The Journal of biological chemistry 56 14988414
2019 SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer. Cancer immunology research 55 31315913
2002 Identification and characterization of SF2000 and SF2001, two new members of the immune receptor SLAM/CD2 family. Immunogenetics 51 11862385
2011 A novel isoform of the Ly108 gene ameliorates murine lupus. The Journal of experimental medicine 50 21422172
2006 2B4 (CD244), NTB-A and CRACC (CS1) stimulate cytotoxicity but no proliferation in human NK cells. International immunology 47 16410313
2013 A role for Ly108 in the induction of promyelocytic zinc finger transcription factor in developing thymocytes. Journal of immunology (Baltimore, Md. : 1950) 46 23355739
2006 Molecular analysis of NTB-A signaling: a role for EAT-2 in NTB-A-mediated activation of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 43 16920955
2007 A pectin methylesterase as an allergenic marker for the sensitization to Russian thistle (Salsola kali) pollen. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 42 17581207
2015 In vivo induction of antioxidant response and oxidative stress associated with genotoxicity and histopathological alteration in two commercial fish species due to heavy metals exposure in northern India (Kali) river. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 40 26191657
2008 Regulation of NK cell activity by 2B4, NTB-A and CRACC. Frontiers in bioscience : a journal and virtual library 40 17981603
2000 Ly108: a new member of the mouse CD2 family of cell surface proteins. Immunogenetics 38 11132158
2015 Negative Regulation of Humoral Immunity Due to Interplay between the SLAMF1, SLAMF5, and SLAMF6 Receptors. Frontiers in immunology 37 25926831
2011 SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells. Autoimmunity 37 21231893
2020 SLAMF6​ deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint. eLife 35 32122464
2015 B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance. Journal of immunology (Baltimore, Md. : 1950) 33 25801429
2019 SLAMF6 clustering is required to augment T cell activation. PloS one 30 31199820
2016 The human 2B4 and NTB-A receptors bind the influenza viral hemagglutinin and co-stimulate NK cell cytotoxicity. Oncotarget 30 26919106
2013 HIV-1 Vpu affects the anterograde transport and the glycosylation pattern of NTB-A. Virology 30 23528733
2016 Slamf6 negatively regulates autoimmunity. Clinical immunology (Orlando, Fla.) 26 27368806
2014 SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death. Journal of immunology (Baltimore, Md. : 1950) 25 24688028
2014 SAP-regulated T Cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions. Journal of immunology (Baltimore, Md. : 1950) 25 25217164
2003 Immunochemical characterization of Russian thistle (Salsola kali) pollen extracts. Purification of the allergen Sal k 1. Allergy 25 14616126
2018 Soluble SLAMF6 Receptor Induces Strong CD8+ T-cell Effector Function and Improves Anti-Melanoma Activity In Vivo. Cancer immunology research 24 29305520
2017 T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell-Cell Contact Mediated through SLAMF6 and SAP. Journal of immunology (Baltimore, Md. : 1950) 24 28904129
2010 Sal k 4, a new allergen of Salsola kali, is profilin: a predictive value of conserved conformational regions in cross-reactivity with other plant-derived profilins. Bioscience, biotechnology, and biochemistry 24 20622444
2013 NK cell cytotoxicity mediated by 2B4 and NTB-A is dependent on SAP acting downstream of receptor phosphorylation. Frontiers in immunology 23 23346089
2012 CD3-T cell receptor co-stimulation through SLAMF3 and SLAMF6 receptors enhances RORγt recruitment to the IL17A promoter in human T lymphocytes. The Journal of biological chemistry 23 22989874
2013 Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 23629864
2010 Identification of methionine synthase (Sal k 3), as a novel allergen of Salsola kali pollen. Molecular biology reports 21 20238167
2016 A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells. Oncotarget 19 27029059
2014 Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice. Journal of autoimmunity 19 24508410
2022 SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization. Oncology letters 17 35126725
2016 CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development. PloS one 17 27258160
2022 SLAMF6 compartmentalization enhances T cell functions. Life science alliance 16 36622343
2007 The lymphoid cell surface receptor NTB-A: a novel monoclonal antibody target for leukaemia and lymphoma therapeutics. British journal of haematology 16 17456053
2021 Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions. Cancer immunology research 15 33762352
2013 Sal k 5, a member of the widespread Ole e 1-like protein family, is a new allergen of Russian thistle (Salsola kali) pollen. International archives of allergy and immunology 15 24356442
2015 The cell surface receptor Slamf6 modulates innate immune responses during Citrobacter rodentium-induced colitis. International immunology 12 25957267
2015 A recombinant Sal k 1 isoform as an alternative to the polymorphic allergen from Salsola kali pollen for allergy diagnosis. International archives of allergy and immunology 12 26202069
2012 Characterization of Ly108 in the thymus: evidence for distinct properties of a novel form of Ly108. Journal of immunology (Baltimore, Md. : 1950) 12 22393150
2010 Expression of the recombinant major allergen of Salsola kali pollen (Sal k 1) and comparison with its low-immunoglobulin E-binding mutant. Allergology international : official journal of the Japanese Society of Allergology 12 20414052
2012 The natural profilin from Russian thistle (Salsola kali) contains a low IgE-binding ability isoform--molecular and immunological characterization. The FEBS journal 11 23043287
2024 Clinical and immunological relevance of SLAMF6 expression in the tumor microenvironment of breast cancer and melanoma. Scientific reports 10 38287061
2017 A relevant IgE-reactive 28kDa protein identified from Salsola kali pollen extract by proteomics is a natural degradation product of an integral 47kDa polygalaturonase. Biochimica et biophysica acta. Proteins and proteomics 10 28502749
2021 Remote sensing-based water quality index estimation using data-driven approaches: a case study of the Kali River in Uttar Pradesh, India. Environment, development and sustainability 9 33897276
2020 Urinary Cell Transcriptome Profiling and Identification of ITM2A, SLAMF6, and IKZF3 as Biomarkers of Acute Rejection in Human Kidney Allografts. Transplantation direct 9 32766436
2017 Invariant NKT Cell Activation Is Potentiated by Homotypic trans-Ly108 Interactions. Journal of immunology (Baltimore, Md. : 1950) 6 28373584
2021 Expression and function of SLAMF6 in CD8+ T lymphocytes of patients with severe aplastic anemia. Cellular immunology 5 33774556
2018 Design and evaluation of a hypoallergenic peptide-based vaccine for Salsola kali allergy. International immunopharmacology 5 30445308
2022 SLAMF6 is associated with the susceptibility and severity of rheumatoid arthritis in the Chinese population. Journal of orthopaedic surgery and research 4 35016729
2010 The Russian Thistle (Salsola kali) pollen major allergen, Sal k 1, can be quantified in allergenic extracts and airborne pollen. International archives of allergy and immunology 4 20185924
2022 Risk assessment and spatio-temporal distribution of dissolved trace metals in Swarna, Sharavati and Kali estuaries, South-West Coast of India. Environmental science and pollution research international 3 36066797
2025 Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia. Nature cancer 2 41044242
2024 Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling. bioRxiv : the preprint server for biology 2 38746459
2024 The cytoskeletal protein profilin is an important allergen in saltwort (Salsola kali). Frontiers in immunology 2 38911871
2018 Production of Recombinant Protein of Salsola Kali (Sal k1) Pollen Allergen in Lactococcus Lactis. Iranian journal of allergy, asthma, and immunology 2 29757586
1986 [Nutritional behavior of insulin-dependent diabetes patients studied with the KALI 2.1.2 computer program]. Zeitschrift fur Ernahrungswissenschaft 2 3014761
2025 SLAMF6 regulates basal T cell receptor signaling and influences invariant natural killer T cell lineage diversity. International immunology 1 40405353
2025 Assessing Genetic Risk of DKK3 and SLAMF6 in Erectile Dysfunction: A Comprehensive Analysis Based on Mendelian Randomization. American journal of men's health 1 40888559
2025 Identification of methylation-related genes and the potential regulatory mechanism of SLAMF6 in CMS4 colorectal cancer. Clinical epigenetics 1 41044679
2024 TCF1highPD-1+Ly108+CD8+ T Cells Are Associated with Graft Preservation in Sensitized Mice Treated with Non-Fc Receptor-Binding CD3 Antibodies. ImmunoHorizons 1 38587418
2024 NTB-A and 2B4 Natural Killer Cell Receptors Modulate the Capacity of a Cocktail of Non-Neutralizing Antibodies and a Small CD4-Mimetic to Eliminate HIV-1-Infected Cells by Antibody-Dependent Cellular Cytotoxicity. Viruses 1 39066329
2023 Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice. International journal of molecular sciences 1 36902453
2016 Enhanced Synthesis of Curculigoside by Stress and Amino Acids in Static Culture of Curculigo orchioides Gaertn (Kali Musli). Pharmacognosy research 1 27365988
1987 [Nutritional behavior of non-insulin-dependent type II diabetes patients using the KALI 2.1.2 computer program]. Zeitschrift fur Ernahrungswissenschaft 1 3630248
2026 SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer. Nature 0 41673151
2025 SLAMF6 enables efficient attachment, synapse formation, and killing of HIV-1-infected CD4+ T cells by virus-specific CD8+ T cells. bioRxiv : the preprint server for biology 0 39896504
2025 Geomorphic investigation of glacial and paraglacial landforms in the upper catchment of the Kali Ganga River, Tethyan Himalaya, Uttarakhand, India. Environmental monitoring and assessment 0 40387960
2025 Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion. Cells 0 40558528
2024 Designing a T-cell epitope-based vaccine using in silico approaches against the Sal k 1 allergen of Salsola kali plant. Scientific reports 0 38424208
2018 [A preliminary study on SLAMF6 expression in patients with severe aplastic anemia]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 30486590