Affinage

LY9

T-lymphocyte surface antigen Ly-9 · UniProt Q9HBG7

Length
655 aa
Mass
72.1 kDa
Annotated
2026-06-10
59 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LY9 (CD229/SLAMF3) is a homophilic cell-surface receptor of the SLAM family that uses tyrosine phosphorylation of its cytoplasmic tail to assemble distinct signaling complexes and tune both adaptive and innate immune cell behavior (PMID:11389028, PMID:15905546, PMID:15879090). Its N-terminal Ig domain mediates homophilic self-adhesion through defined charged residues (E27, E29, R89) and drives receptor relocalization to the T–B immunological synapse (PMID:15905546). The phosphorylated tail recruits the adaptor SAP/SH2D1A, which in turn binds and activates FynT to couple LY9 to Src-family kinase signaling (PMID:11389028, PMID:15096483); a separate phosphotyrosine (Y606) engages Grb2 to drive receptor endocytosis and to attenuate TCR-driven ERK and NFAT signaling (PMID:15879090), while a Y470EKL motif binds the AP-2/clathrin adaptor to control internalization independently of SAP recruitment (PMID:12621057). As a T-cell costimulator, LY9 ligation promotes CD4+ T-cell IL-17 production through SAP-dependent recruitment of RORγt to the IL17A promoter and JAK1/STAT3 activation (PMID:22184727, PMID:22989874, PMID:38061117), enhances IL-2 sensitivity and Treg differentiation via a Smad3/STAT5 axis (PMID:27482100), and polarizes naive CD4+ T cells toward IFN-γ-producing TH1* memory cells by inducing T-bet via SAP and RORγT independently of SAP, with TCR-driven IFN-γ requiring NFAT1 and RORγT (PMID:40446017). Loss-of-function studies establish LY9 as a negative regulator of innate-like lymphocyte development, restraining thymic innate CD8+ T cells, iNKT cells, and marginal-zone/B1 B cells through IL-4-dependent and IL-4-independent mechanisms, with its deficiency leading to autoantibody production (PMID:23225888, PMID:23914190, PMID:26667173, PMID:28980301). On macrophages LY9 functions as a 'don't eat me' checkpoint, inhibiting phagocytosis of hematopoietic cells via SHP-1/2-mediated suppression of LRP1/mTOR/Syk pro-phagocytic signals (PMID:35061505), and in multiple myeloma its homophilic self-ligation drives RAS/ERK proliferative signaling through SHP2–GRB2 and RASAL3 complexes (PMID:31974290, PMID:36445333). Autosomal recessive LY9 deficiency in humans selectively impairs IFN-γ production by TH1* CD4+ memory T cells, underlying susceptibility to Mycobacterium tuberculosis (PMID:40446017).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2001 High

    Established the proximal signaling logic of LY9 by showing its cytoplasmic tail recruits the adaptor SAP in a tyrosine-phosphorylation-dependent manner, defining LY9 as a SLAM-family receptor coupled to SAP-based signaling.

    Evidence Yeast two-hybrid, COS cell co-transfection, and lymphoid cell biochemistry

    PMID:11389028

    Open questions at the time
    • Did not identify the kinase phosphorylating LY9
    • Downstream effectors of recruited SAP not yet defined
  2. 2003 High

    Resolved how LY9 surface levels are controlled by mapping a Y470EKL motif that binds the AP-2/clathrin adaptor to drive internalization separately from SAP recruitment, linking receptor signaling to receptor trafficking.

    Evidence Co-IP of AP-2, Y470 mutagenesis, and internalization assays with TCR/BCR co-ligation

    PMID:12621057

    Open questions at the time
    • Functional consequence of endocytosis for signaling outcome not established
    • Did not connect trafficking to a specific T-cell response
  3. 2004 High

    Defined the mechanism by which SAP transduces LY9 signals, showing SAP bridges the receptor to FynT (via SH3 and kinase domains) and directly increases FynT catalytic activity, with the R78E mutant abolishing both bridging and kinase activation.

    Evidence In vitro kinase reconstitution, yeast two-hybrid/pull-down, and SAP mutant transfection in primary T cells

    PMID:15096483

    Open questions at the time
    • Substrates of FynT downstream of LY9 not mapped
    • Relative contribution of Lck versus FynT not resolved
  4. 2005 High

    Demonstrated that LY9 is a homophilic ligand acting through its N-terminal Ig domain and that it relocalizes to the immunological synapse, establishing the structural basis for self-recognition between apposing cells.

    Evidence Soluble CD229-Ig binding, B-C/F-G loop point mutagenesis (E27, E29, R89), and confocal synapse imaging

    PMID:15905546

    Open questions at the time
    • Affinity of the homophilic interaction not quantified
    • How homophilic engagement triggers tail phosphorylation not shown
  5. 2005 High

    Identified a second, SAP-independent signaling branch in which phospho-Y606 recruits Grb2 to drive LY9 endocytosis and to attenuate TCR-driven ERK and NFAT signaling, revealing LY9 as a negative modulator of T-cell activation.

    Evidence Reciprocal Co-IP, phosphotyrosine mapping, dominant-negative Grb2, NFAT-luciferase and endocytosis assays

    PMID:15879090

    Open questions at the time
    • Mechanistic link between Grb2 binding and ERK attenuation not fully traced
    • Interplay between Grb2 and AP-2 trafficking pathways unresolved
  6. 2006 Medium

    Genetic dissection in Ly9-knockout mice revealed a non-redundant role distinct from SLAM and SAP, with defective IL-4/Th2 responses and impaired T-cell proliferation but normal NKT development and viral responses.

    Evidence Ly9 KO mouse with in vitro T-cell stimulation and cytokine measurement, compared to SLAM-/- and SAP-/-

    PMID:16365421

    Open questions at the time
    • Molecular basis of the IL-4 defect not defined
    • Single lab, phenotype not yet mechanistically connected to signaling complexes
  7. 2007 Medium

    Antibody ligation of CD229 was shown to suppress activation markers and cytokine output, providing functional evidence that LY9 acts as an inhibitory co-receptor on T cells.

    Evidence In vitro anti-CD229 mAb stimulation with flow cytometric CD69/CD25 and cytokine readouts

    PMID:17919264

    Open questions at the time
    • Single method, single lab
    • Inhibitory mechanism at the signaling level not dissected
  8. 2012 High

    Mouse genetics established LY9 as a negative regulator of innate-like lymphocyte development, with IL-4 signaling placed downstream by epistasis, reframing LY9 as a brake on thymic innate CD8+ T cell and iNKT expansion.

    Evidence Ly9 KO analysis, gene expression profiling, Ly9-/-IL4ra-/- double-KO epistasis, and in vivo anti-Ly9 mAb

    PMID:23225888

    Open questions at the time
    • The receptor-proximal signal restraining innate lineages not specified
    • IL-4-independent component not molecularly defined
  9. 2011 Medium

    Functional costimulation studies showed LY9 co-engagement with CD3 drives IL-17 production in CD4+ T cells in a SAP-dependent manner, connecting LY9 to Th17 effector programs.

    Evidence In vitro anti-SLAMF3/SLAMF6 co-stimulation with IL-17 measurement and SAP-dependence

    PMID:22184727

    Open questions at the time
    • Transcriptional mechanism not yet identified at this stage
    • Naive versus memory contributions only partially separated
  10. 2012 Medium

    Defined the transcriptional output of LY9 Th17 costimulation by showing recruitment of RORγt to the IL17A promoter cooperating with the CD28/NFAT1 pathway, attributing dominance to increased nuclear RORγt.

    Evidence ChIP of NFAT1 and RORγt at IL17A promoter, nuclear fractionation, and T-cell costimulation

    PMID:22989874

    Open questions at the time
    • Upstream signal driving RORγt nuclear accumulation not mapped
    • Single lab
  11. 2013 Medium

    Extended the inhibitory-receptor model to autoimmunity by showing Ly9 deficiency yields spontaneous anti-nuclear autoantibodies and Tfh/GC expansion, with LY9 suppressing CD4+ IFN-γ production.

    Evidence Ly9 KO phenotyping (ANA, anti-dsDNA), Tfh/GC flow cytometry on two backgrounds, in vitro cytokine assay

    PMID:23914190

    Open questions at the time
    • Causal link between IFN-γ suppression and autoantibody formation not established
    • Cell-intrinsic versus extrinsic effects not separated
  12. 2015 Medium

    B-cell-focused genetics revealed LY9 restrains marginal-zone, B1a, and transitional B cell compartments and natural antibody output, with in vivo mAb targeting selectively depleting these subsets Fc-independently.

    Evidence Ly9 KO phenotyping, in vivo anti-Ly9 mAb, TNP-Ficoll immunization, serum antibody measurement

    PMID:26667173

    Open questions at the time
    • Signaling pathway controlling B-cell subset homeostasis not defined
    • CD19/CD21/CD81 downregulation mechanism unknown
  13. 2015 Medium

    Linked an SLE-associated coding variant to receptor function by showing the Met602 allele binds SAP with ~2-fold higher affinity than Val602, while Val602 shows higher surface expression and diminished activation, providing a molecular handle on disease association.

    Evidence Binding affinity measurement and T-cell line expression/CD69 activation assays

    PMID:26221972

    Open questions at the time
    • In vivo consequence of altered SAP affinity not demonstrated
    • Single lab, single cell system
  14. 2016 Medium

    Established additional positive-costimulatory branches in which LY9 promotes IL-2 sensitivity and Treg differentiation via a Smad3-dependent CD25/STAT5 mechanism, broadening its role beyond inhibition.

    Evidence In vitro T-cell stimulation, Smad3 inhibition, STAT5 phosphorylation, and Treg differentiation assays

    PMID:27482100

    Open questions at the time
    • How a single receptor produces both inhibitory and costimulatory outcomes not reconciled
    • Smad3 activation mechanism downstream of LY9 unclear
  15. 2013 Medium

    Opened a tumor-suppressor role for LY9 in hepatocellular carcinoma, showing SLAMF3 restoration inhibits proliferation/migration and reduces ERK/JNK/mTOR phosphorylation.

    Evidence siRNA KD/OE in HCC lines, proliferation/apoptosis/migration assays, xenograft, and pathway Western blots

    PMID:24376606

    Open questions at the time
    • Receptor-proximal mechanism in hepatocytes not defined
    • Why LY9 is tumor-suppressive in HCC but proliferative in myeloma unexplained
  16. 2016 Medium

    Detailed the antiproliferative HCC mechanism by linking SLAMF3 to RB hypophosphorylation, E2F inactivation, and PLK1 repression, with patient-sample correlation supporting the axis.

    Evidence RB phosphorylation/E2F/PLK1 analysis with SLAMF3 overexpression and patient correlation

    PMID:26799423

    Open questions at the time
    • Connection between surface receptor and RB/E2F not mechanistically bridged
    • Single lab
  17. 2016 Medium

    Identified a chemosensitization function in which SLAMF3 specifically lowers MRP-1 drug-efflux transporter expression, inversely correlated in patient samples.

    Evidence MRP-1 expression/function and drug sensitivity assays in SLAMF3-overexpressing HCC cells with IHC correlation

    PMID:27081035

    Open questions at the time
    • Mechanism linking SLAMF3 to MRP-1 regulation unknown
    • Specificity over other transporters not mechanistically explained
  18. 2014 Medium

    Revealed a pathogen-exploited function by showing SLAMF3's first extracellular domain binds HCV envelope E2 to facilitate hepatocyte entry.

    Evidence siRNA KD, OE, blocking antibody, domain peptide competition, recombinant E2 binding, and HCV infectivity assays

    PMID:24927415

    Open questions at the time
    • Whether LY9 is an obligate entry factor or accessory not resolved
    • Structural basis of the E2 interaction not determined
  19. 2017 Medium

    Refined the innate-lymphocyte role by showing LY9 negatively regulates iNKT lineage choice, restraining NKT2 expansion and enabling NKT1 development.

    Evidence Ly9 KO on two backgrounds, iNKT subset flow cytometry, and in vivo agonistic anti-Ly9 mAb with cytokine readouts

    PMID:28980301

    Open questions at the time
    • Signal controlling NKT1/NKT2 balance not molecularly defined
    • Cell-intrinsic versus thymic-niche effects not separated
  20. 2019 Medium

    Identified a regulatory input controlling LY9 expression, showing palmitic acid induces SLAMF3 upregulation through STAT5-PI3K/Akt signaling on T cells.

    Evidence Palmitic acid treatment, RNA-seq, and PI3K/Akt and STAT5 inhibitor studies

    PMID:31332162

    Open questions at the time
    • Functional consequence of metabolite-driven upregulation for immunity not tested
    • Direct transcriptional control of LY9 not mapped
  21. 2020 High

    Established the oncogenic signaling mechanism in multiple myeloma, showing SLAMF3 homophilic self-ligation recruits SHP2 and GRB2 to activate MAPK/ERK and drive proliferation and drug resistance.

    Evidence Reciprocal Co-IP of SHP2/GRB2, KD/KO, cytoplasmic truncation, pERK Western, SHP2 inhibitor, and xenograft

    PMID:31974290

    Open questions at the time
    • How identical homophilic ligation produces opposite outcomes in T cells versus myeloma not resolved
    • Order of SHP2/GRB2 assembly on the tail not defined
  22. 2022 Medium

    Expanded the myeloma RAS/ERK mechanism by identifying RASAL3 as a CD229 interactor through which intercellular tyrosine phosphorylation self-activates the receptor.

    Evidence Co-IP/mass spectrometry, RASAL3 validation, co-culture immunofluorescence, RAS/ERK analysis, and xenograft

    PMID:36445333

    Open questions at the time
    • Direct biochemical role of RASAL3 in ERK activation not fully resolved
    • Single lab
  23. 2022 High

    Defined LY9 as a macrophage 'don't eat me' checkpoint, inhibiting phagocytosis of hematopoietic cells via SHP-1/2-mediated suppression of LRP1/mTOR/Syk, with epistasis to CD47.

    Evidence SFR-deficient mouse models, phagocytosis assays, LRP1/mTOR/Syk signaling analysis, and combined SFR/CD47 deletion

    PMID:35061505

    Open questions at the time
    • Individual contribution of LY9 versus SLAMF4 to the macrophage checkpoint not isolated
    • Ligand triggering the inhibitory signal on macrophages not defined
  24. 2022 Medium

    Connected LY9 loss to therapy resistance in HCC, showing SLAMF3 reverses EMT and restores sorafenib sensitivity through mTOR/ERK1/2 inhibition.

    Evidence Sorafenib-resistant lines, SLAMF3 overexpression rescue, EMT marker and mTOR/ERK analysis, migration assay

    PMID:35205659

    Open questions at the time
    • Receptor-proximal events upstream of mTOR/ERK in hepatocytes still unknown
    • Single lab
  25. 2025 High

    Human loss-of-function genetics established LY9 as essential for IFN-γ production by TH1* CD4+ memory T cells and anti-mycobacterial immunity, integrating SAP-dependent T-bet induction and SAP-independent RORγT/NFAT1 signaling into a coherent costimulatory mechanism.

    Evidence Human AR LY9-deficient patient T-cell assays, T-bet/SAP/RORγT pathway dissection, TH1* polarization, and NFAT1/RORγT requirement

    PMID:40446017

    Open questions at the time
    • Full reconciliation of inhibitory mouse phenotypes with costimulatory human role not complete
    • Why TH1* memory cells are selectively dependent on LY9 not fully explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single homophilic receptor produces opposite outcomes across contexts — inhibitory on T cells and macrophages, tumor-suppressive in HCC, yet proliferative in myeloma — i.e. what dictates assembly of SAP/FynT versus Grb2 versus SHP1/2/SHP2-GRB2-RASAL3 complexes on the same cytoplasmic tail.
  • No unifying structural model of context-dependent adaptor selection
  • Stoichiometry and competition among SAP, Grb2, AP-2, and SHP1/2 on the tail not defined
  • Determinants of cell-type-specific output unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2 GO:0001618 virus receptor activity 1 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
AP-2FYNGRB2LY9RASAL3SH2D1ASHP2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 LY9 (Ly-9) recruits the SAP/SH2D1A protein via specific tyrosine residues in its cytoplasmic tail; this interaction is most efficient when those tyrosines are phosphorylated. Interactions were demonstrated by yeast two-hybrid, COS cell transfections, and in lymphoid cells. Yeast two-hybrid, COS cell transfection, lymphoid cell biochemical assays Blood High 11389028
2004 SAP is required for phosphorylation of Ly9 in thymocytes and peripheral T cells. SAP directly binds FynT (via both SH3 and kinase domains) and Lck (via kinase domain only), and addition of SAP to autoinhibited FynT causes a large increase in FynT catalytic activity in vitro. The SAP mutant R78E, which cannot bind the FynT SH3 domain, neither increases FynT activity nor functions as an adaptor in T cells, demonstrating SAP bridges Ly9 with Src-family kinases. In vitro protein interaction (yeast two-hybrid, pull-down), in vitro kinase activity assay, T-cell transfection with SAP mutants, primary thymocyte/T-cell phosphorylation analysis International immunology High 15096483
2005 CD229 (LY9) binds homophilically through its N-terminal Ig-domain. A soluble CD229-Ig fusion protein bound CD229-transfected cells but not cells expressing other CD150 family receptors. Charged residues E27, E29 (B-C loop) and R89 (F-G loop) of the N-terminal domain are required for homophilic adhesion; mutation R44A enhanced the interaction. Confocal microscopy showed CD229 relocalizes to the T–B cell contact area during antigen-dependent immunological synapse formation. Soluble Ig-fusion protein binding assay, domain deletion and point mutagenesis, confocal microscopy of immune synapse Journal of immunology High 15905546
2005 CD229 interacts with Grb2 in a phosphorylation-dependent manner; the SH2 domain of Grb2 binds tyrosine Y606 of CD229. This interaction is distinct from the SAP-binding motif. CD229 co-precipitates with Grb2 in T lymphocytes after pervanadate treatment and after CD229 or TCR ligation. The Grb2-binding site is required for CD229 internalization; a dominant-negative Grb2 (SH2-domain only) impairs CD229 endocytosis. CD229 ligation partially inhibits ERK phosphorylation and TCR-driven NFAT signaling. Co-immunoprecipitation, phospho-tyrosine mapping, dominant-negative transfection, NFAT-luciferase reporter assay, endocytosis assay Journal of immunology High 15879090
2003 CD229 cell-surface expression is regulated by its interaction with the µ2 chain of the clathrin-associated AP-2 adaptor complex via the Y470EKL motif in its cytoplasmic tail. This motif is required for CD229 internalization but not for SAP recruitment. TCR and BCR signaling increase the rate of CD229 endocytosis; cross-linking with intact (but not F(ab')2) antibodies inhibits internalization on B cells, implicating Fcγ receptors. Co-immunoprecipitation of AP-2 complex, site-directed mutagenesis of Y470, internalization assay, T- and B-cell receptor co-ligation experiments The Journal of biological chemistry High 12621057
2006 Ly9-deficient mice exhibit reduced IL-4 production (Th2 defect) and poor T-cell proliferation with little IL-2 after suboptimal anti-CD3 stimulation in vitro, distinct from SLAM-/- and SAP-/- phenotypes. Ly9-/- macrophages show no cytokine or bacterial killing defects. Ly9-/- mice foster normal NKT cell development and appropriate lymphocytic choriomeningitis virus responses, unlike SAP-/- mice. Ly9 knockout mouse generation, in vitro T-cell stimulation assays, cytokine measurement (IL-4, IL-2), comparison with SLAM-/- and SAP-/- mice Journal of immunology Medium 16365421
2007 Ligation of mouse CD229 with a specific monoclonal antibody inhibited expression of activation markers CD69 and CD25 on T lymphocytes in response to anti-CD3 stimulation in vitro, with concomitant reduction in cytokine production, demonstrating CD229 functions as an inhibitory co-receptor on T cells. In vitro T-cell stimulation with anti-CD229 mAb, flow cytometric measurement of CD69/CD25 and cytokine production Tissue antigens Medium 17919264
2011 SLAMF3 (CD229) co-engagement with CD3 under Th17-polarizing conditions increases IL-17 production in CD4+ T cells, and this effect requires the adaptor molecule SAP. Both naïve and memory CD4+ T cells produce more IL-17 in response to SLAMF3/SLAMF6 co-stimulation than to CD28 co-stimulation. In vitro T-cell stimulation with anti-SLAMF3/SLAMF6 antibodies, cytokine (IL-17) measurement, SAP-dependent signaling analysis Journal of immunology Medium 22184727
2012 CD3/TCR co-stimulation through SLAMF3 (and SLAMF6) recruits the transcription factor RORγt to the IL17A promoter in human T lymphocytes, cooperating with the canonical CD28/NFAT1 pathway to drive IL-17A expression. The dominance of the SLAMF3/SLAMF6 pathway in IL-17A induction is attributed to increased nuclear abundance and promoter recruitment of RORγt. Chromatin immunoprecipitation (ChIP) of NFAT1 and RORγt at IL17A promoter, nuclear fractionation, T-cell co-stimulation assay The Journal of biological chemistry Medium 22989874
2012 Ly9 (CD229) acts as a negative regulator of thymic innate memory-like CD8+ T cell development and invariant NKT cell numbers. Ly9-deficient thymi show expanded innate CD8+ SP cells and increased iNKT cells; gene expression profiling revealed upregulation of IL-4 and PLZF. Double-deficient Ly9-/-IL4ra-/- mice lacked the expanded innate CD8+ subset, placing IL-4 signaling downstream of Ly9. Anti-Ly9 mAb in wild-type mice inhibited IL-4 levels induced by α-galactosylceramide. Ly9 KO mouse analysis, gene expression profiling, Ly9-/-IL4ra-/- double-KO epistasis, mCMV infection model, in vivo anti-Ly9 mAb treatment Journal of immunology High 23225888
2013 Ly9-deficient mice spontaneously develop anti-nuclear, anti-dsDNA, and anti-nucleosome autoantibodies on both B6.129 and BALB/c.129 backgrounds, with expansion of T follicular helper and germinal center B cells in aged mice. In vitro experiments showed Ly9 acts as an inhibitory receptor suppressing IFN-γ production by CD4+ T cells. Ly9 KO mouse phenotyping (ANA, anti-dsDNA ELISA), flow cytometry of Tfh and GC B cells, in vitro CD4+ T-cell cytokine assay Frontiers in immunology Medium 23914190
2013 SLAMF3 expression in hepatocytes inhibits HCC cell proliferation and migration, promotes apoptosis, and suppresses xenograft progression. SLAMF3 restoration decreases phosphorylation of MAPK ERK1/2, JNK, and mTOR in HCC cell lines. siRNA knockdown/overexpression in HCC cell lines, proliferation/apoptosis/migration assays, nude mouse xenograft, Western blot of ERK/JNK/mTOR phosphorylation PloS one Medium 24376606
2014 SLAMF3 (CD229) interacts with HCV envelope protein E2 via its first N-terminal extracellular domain, and this interaction facilitates HCV entry into hepatocytes. siRNA knockdown and blocking antibodies against SLAMF3 decrease hepatocyte susceptibility to HCV infection, while overexpression increases susceptibility. Recombinant E2 binds SLAMF3 and anti-SLAMF3 antibodies inhibit this interaction. siRNA knockdown, SLAMF3 overexpression, blocking antibody, domain peptide competition, recombinant E2 binding assay, HCV infectivity assay PloS one Medium 24927415
2015 In Ly9-deficient mice, splenic transitional 1, marginal zone, and B1a B cells are expanded; bone marrow B cell development is unaltered. Ly9-/- mice show elevated IgG3 natural antibodies and increased T-independent type II antibody responses. Anti-Ly9 mAb administered to wild-type mice selectively eliminates MZ B cells, reduces B1 and T1 B cells, downregulates the CD19/CD21/CD81 complex, and impairs B cell survival and activation in an Fc-independent manner. Ly9 KO mouse phenotyping, flow cytometry, in vivo mAb treatment, TNP-Ficoll immunization, serum Ab measurement Journal of immunology Medium 26667173
2015 The SLE-associated Met602 variant of CD229 (rs509749) has approximately two-fold higher affinity for SAP compared with the Val602 variant. Val602 CD229 is more highly expressed on the T-cell surface than Met602 CD229. Cells expressing Val602 show diminished activation (CD69 upregulation) compared with Met602 cells. Surface plasmon resonance/binding affinity assay, T-cell line expression analysis, CD69 activation assay Immunology Medium 26221972
2016 SLAMF3 ligation on CD4+ T cells promotes sensitivity to IL-2 by upregulating CD25 via a Smad3-dependent mechanism, enhancing the IL-2/IL-2R/STAT5 signaling pathway and cell proliferation. SLAMF3 costimulation also promotes Treg differentiation from naïve CD4+ T cells. In vitro T-cell stimulation, CD25 surface measurement, Smad3 inhibition, STAT5 phosphorylation assay, Treg differentiation assay Proceedings of the National Academy of Sciences Medium 27482100
2016 SLAMF3 overexpression in HCC cells retains the Retinoblastoma (RB) factor in its hypophosphorylated (active) form, leading to inactivation of E2F transcription factor and repression of PLK1 expression and activation, thereby inhibiting mitosis and proliferation. An inverse correlation between SLAMF3 and PLK1 expression was observed in HCC patient samples. Western blot of RB phosphorylation, E2F activity assay, PLK1 expression analysis, SLAMF3 overexpression in HCC cells, patient sample correlation Oncotarget Medium 26799423
2016 SLAMF3 overexpression in HCC cells specifically reduces MRP-1 (multidrug resistance protein 1) expression and its function as a drug efflux transporter, without affecting ABCG2 or MDR expression. This correlates inversely with MRP-1 expression in HCC patient samples, and sensitizes cells to anti-cancer drugs. Western blot, flow cytometry of MRP-1 expression/function, drug sensitivity assay in SLAMF3-overexpressing HCC cells, patient sample IHC correlation Oncotarget Medium 27081035
2017 Ly9 (SLAMF3) negatively regulates iNKT cell lineage differentiation. Ly9-deficient BALB/c mice show expanded thymic NKT2 cells with near-absent NKT1 cells. Anti-Ly9 agonistic mAb in wild-type mice impairs IL-4 and IFN-γ production and reduces splenic iNKT cells, with significant decrease in NKT2 proportion. Ly9 KO mouse analysis on BALB/c and C57BL/6 backgrounds, flow cytometry of iNKT subsets, in vivo anti-Ly9 agonistic mAb treatment, cytokine measurement European journal of immunology Medium 28980301
2019 Palmitic acid induces SLAMF3 upregulation on human T cells through the STAT5-PI3K/Akt signaling pathway. Inhibition of PI3K/Akt or its upstream mediator STAT5 prevents palmitic acid-induced SLAMF3 upregulation, establishing this pathway as a regulatory mechanism of SLAMF3 expression. Palmitic acid treatment of T cells and Jurkat cells, RNA sequencing, PI3K/Akt and STAT5 inhibitor studies, flow cytometry of SLAMF3 expression Cell death & disease Medium 31332162
2020 SLAMF3 in multiple myeloma cells interacts directly with adaptor proteins SHP2 and GRB2 (which also interact with each other), activating the MAPK/ERK signaling pathway to promote myeloma proliferation and drug resistance. SLAMF3 knockdown/knockout or cytoplasmic domain truncation decreases phosphorylated ERK and suppresses proliferation. Self-ligand (homophilic CD229–CD229) interaction between MM cells mediates this activation. Co-immunoprecipitation of SHP2 and GRB2 with SLAMF3, SLAMF3 KD/KO, cytoplasmic domain truncation mutant, Western blot of pERK, SHP2 inhibitor treatment, xenograft model Molecular cancer research High 31974290
2022 SLAMF3 and SLAMF4 function as 'don't eat me' receptors on macrophages, inhibiting macrophage phagocytosis of hematopoietic cells through SH2-domain-containing phosphatases (SHP-1/2). These receptors inhibit 'eat me' signals including LRP1-mediated mTOR and Syk activation. SFR deficiency triggers macrophage phagocytosis of hematopoietic cells and combined deletion of SFRs and CD47 causes hematopoietic cytopenia. SFR-deficient mouse models, phagocytosis assays, LRP1/mTOR/Syk signaling analysis, combined SFR/CD47 deletion, hematopoietic graft rejection model Science immunology High 35061505
2022 CD229 promotes MM cell proliferation via the RAS/ERK signaling pathway. Co-immunoprecipitation coupled with mass spectrometry identified RASAL3 as a downstream interacting protein of CD229. Intercellular tyrosine phosphorylation mediates self-activation of CD229 which activates RAS/ERK signaling through RASAL3. Co-immunoprecipitation coupled with mass spectrometry, RASAL3 interaction validation, immunofluorescence co-culture assay, RAS/ERK pathway analysis, xenograft mouse model Aging Medium 36445333
2022 Loss of SLAMF3 expression corresponds to sorafenib-resistant phenotypes in HCC cells undergoing epithelial-to-mesenchymal transition (EMT). Overexpression of SLAMF3 in resistant cells reverses EMT, decreases metastatic potential, and inhibits mTOR/ERK1/2 signaling, restoring sorafenib sensitivity. Sorafenib-resistant cell line generation, flow cytometry and Western blot of SLAMF3 and EMT markers, SLAMF3 overexpression, mTOR/ERK1/2 pathway analysis, migration assay Cancers Medium 35205659
2023 SLAMF3 co-stimulation promotes CD4+ T cell differentiation toward Th17 cells and IL-17A secretion via enrichment of RORγt and activation of the JAK1/STAT3 pathway. The drug iguratimod reverses SLAMF3-induced Th17 differentiation by inhibiting pJAK1 and pSTAT3. Anti-CD3/SLAMF3 T-cell stimulation, Th17 differentiation assay, RNA sequencing, Western blot of RORγt/pJAK1/pSTAT3, JAK1 inhibitor (iguratimod) treatment International immunopharmacology Medium 38061117
2025 Autosomal recessive LY9 deficiency in humans causes selective impairment of IFN-γ production by TH1* (CCR4-CCR6+CXCR3+T-bet+RORγT+) CD4+ memory T cells, underlying susceptibility to Mycobacterium tuberculosis. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via SAP and RORγT without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1* cells in a T cell-intrinsic manner via NFAT1 and RORγT. Human AR LY9-deficient patient T-cell functional assays, T-bet/SAP/RORγT pathway analysis, in vitro TH1* polarization, NFAT1 and RORγT requirement established, TCR co-stimulation assays Science immunology High 40446017
2008 A non-synonymous SNP rs509749 in exon 8 of LY9 (encoding Val/Met at position 602 in the cytoplasmic domain within the SAP/SH2D1a consensus binding site) is associated with SLE susceptibility and skews T-cell populations in Canadian SLE family members carrying the risk allele, increasing CD8+ memory T cells while decreasing CD4+ naïve and activated T cells. Family-based association study, T-cell phenotyping by flow cytometry in SLE families stratified by rs509749 genotype Genes and immunity Low 18216865

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood 100 11389028
2006 Ly9 (CD229)-deficient mice exhibit T cell defects yet do not share several phenotypic characteristics associated with SLAM- and SAP-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 73 16365421
2005 CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 73 15905546
2004 Differential expression of SAP and EAT-2-binding leukocyte cell-surface molecules CD84, CD150 (SLAM), CD229 (Ly9) and CD244 (2B4). Tissue antigens 73 15245368
2020 CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide. Nature communications 68 32034142
2008 Association of LY9 in UK and Canadian SLE families. Genes and immunity 67 18216865
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
2022 SLAMF3 and SLAMF4 are immune checkpoints that constrain macrophage phagocytosis of hematopoietic tumors. Science immunology 58 35061505
2011 Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma. Haematologica 57 21606160
2001 Molecular characterization and expression of a novel human leukocyte cell-surface marker homologous to mouse Ly-9. Blood 56 11369645
1992 Isolation and characterization of cDNA clones for mouse Ly-9. Journal of immunology (Baltimore, Md. : 1950) 52 1506686
2004 SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9. International immunology 51 15096483
2015 Utility of CD54, CD229, and CD319 for the identification of plasma cells in patients with clonal plasma cell diseases. Cytometry. Part B, Clinical cytometry 45 26130131
2011 Human cytomegalovirus UL7, a homologue of the SLAM-family receptor CD229, impairs cytokine production. Immunology and cell biology 42 21670740
2005 Identification of Grb2 as a novel binding partner of the signaling lymphocytic activation molecule-associated protein binding receptor CD229. Journal of immunology (Baltimore, Md. : 1950) 39 15879090
1995 Physical and genetic linkage of the genes encoding Ly-9 and CD48 on mouse and human chromosomes 1. Immunogenetics 34 7797269
2012 Cutting edge: Ly9 (CD229), a SLAM family receptor, negatively regulates the development of thymic innate memory-like CD8+ T and invariant NKT cells. Journal of immunology (Baltimore, Md. : 1950) 33 23225888
1996 Isolation and characterization of cDNA clones for Humly9: the human homologue of mouse Ly9. Immunogenetics 33 8537117
1980 A monoclonal antibody detecting the Ly-9.2 (Lgp 100) cell-membrane alloantigen. Immunogenetics 33 6160098
2016 Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proceedings of the National Academy of Sciences of the United States of America 32 27482100
2015 CD229 is expressed on the surface of plasma cells carrying an aberrant phenotype and chemotherapy-resistant precursor cells in multiple myeloma. Human vaccines & immunotherapeutics 32 26001047
2023 Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity. Science translational medicine 31 37467316
2013 Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens. Frontiers in immunology 30 23914190
2013 Systemic lupus erythematosus immune complexes increase the expression of SLAM family members CD319 (CRACC) and CD229 (LY-9) on plasmacytoid dendritic cells and CD319 on CD56(dim) NK cells. Journal of immunology (Baltimore, Md. : 1950) 30 23956418
2019 Upregulation of SLAMF3 on human T cells is induced by palmitic acid through the STAT5-PI3K/Akt pathway and features the chronic inflammatory profiles of type 2 diabetes. Cell death & disease 29 31332162
2003 The cell surface expression of SAP-binding receptor CD229 is regulated via its interaction with clathrin-associated adaptor complex 2 (AP-2). The Journal of biological chemistry 26 12621057
2002 Mouse novel Ly9: a new member of the expanding CD150 (SLAM) family of leukocyte cell-surface receptors. Immunogenetics 25 12242590
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 Identification of SLAMF3 (CD229) as an inhibitor of hepatocellular carcinoma cell proliferation and tumour progression. PloS one 20 24376606
2022 CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma. Cancers 19 35565280
2007 Characterization of mouse CD229 (Ly9), a leukocyte cell surface molecule of the CD150 (SLAM) family. Tissue antigens 19 17919264
2020 SLAMF3-Mediated Signaling via ERK Pathway Activation Promotes Aggressive Phenotypic Behaviors in Multiple Myeloma. Molecular cancer research : MCR 18 31974290
2015 Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses. Journal of immunology (Baltimore, Md. : 1950) 18 26667173
2016 Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs. Oncotarget 17 27081035
2000 Gene structure of the mouse leukocyte cell surface molecule Ly9. Immunogenetics 17 10970093
2018 Evaluation of CD229 as a new alternative plasma cell gating marker in the flow cytometric immunophenotyping of monoclonal gammopathies. Cytometry. Part B, Clinical cytometry 16 29316178
2006 Human Ly9 (CD229) as novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (B-CLL) recognized by autologous CD8+ T cells. Experimental hematology 16 16797413
2015 A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T-cell activation. Immunology 15 26221972
2018 The role of surface molecule CD229 in Multiple Myeloma. Clinical immunology (Orlando, Fla.) 14 30326256
2011 Extracellular production of beta-amylase by a halophilic isolate, Halobacillus sp. LY9. Journal of industrial microbiology & biotechnology 14 21505914
2016 RB/PLK1-dependent induced pathway by SLAMF3 expression inhibits mitosis and control hepatocarcinoma cell proliferation. Oncotarget 13 26799423
2022 Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition. Cancers 12 35205659
2018 Ly9 (CD229) Antibody Targeting Depletes Marginal Zone and Germinal Center B Cells in Lymphoid Tissues and Reduces Salivary Gland Inflammation in a Mouse Model of Sjögren's Syndrome. Frontiers in immunology 11 30519241
2017 Ly9 (SLAMF3) receptor differentially regulates iNKT cell development and activation in mice. European journal of immunology 11 28980301
2025 Human LY9 governs CD4+ T cell IFN-γ immunity to Mycobacterium tuberculosis. Science immunology 9 40446017
2024 A review: Mechanisms and molecular pathways of signaling lymphocytic activation molecule family 3 (SLAMF3) in immune modulation and therapeutic prospects. International immunopharmacology 9 38626547
2019 Viral CD229 (Ly9) homologs as new manipulators of host immunity. Journal of leukocyte biology 9 30791129
2023 SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome. International immunopharmacology 8 38061117
2022 Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade. British journal of cancer 8 35618786
2019 The Checkpoint Regulator SLAMF3 Preferentially Prevents Expansion of Auto-Reactive B Cells Generated by Graft-vs.-Host Disease. Frontiers in immunology 8 31057553
2014 The expression of the hepatocyte SLAMF3 (CD229) receptor enhances the hepatitis C virus infection. PloS one 6 24927415
2025 RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC+ Tumor-Associated Macrophages. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40448626
2022 Utility of CD229 as novel marker in measurable residual disease assessment in multiple myeloma-An evidence-based approach. International journal of laboratory hematology 4 36403963
2022 CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation. Aging 4 36445333
2020 The SLAMF3 rs509749 polymorphism correlates with malignant potential in multiple myeloma. Experimental hematology 4 32818503
2025 Bicistronic CAR T Cell against BCMA and CD229 Effectively Controls Myeloma Even When BCMA Expression Is Limited. Cancer immunology research 3 40576564
2023 Combination of CD49b and CD229 Reveals a Subset of Multipotent Progenitors With Short-Term Activity Within the Hematopoietic Stem Cell Compartment. Stem cells translational medicine 3 37706539
2023 Transcriptomic analysis of B cells suggests that CD70 and LY9 may be novel features in patients with systemic lupus erythematosus. Heliyon 2 37144201
2025 Proteome-wide mendelian randomization identifies FCRL3 and LY9 as potential therapeutic targets for lymphoma. Discover oncology 1 41222800

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