Affinage

CD244

Natural killer cell receptor 2B4 · UniProt Q9BZW8

Audit flag: ungrounded claim
Length
370 aa
Mass
41.6 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD244 (2B4/SLAMF4) is a SLAM-family immunoreceptor that binds CD48 and tunes the activation threshold of NK cells, cytotoxic T cells, and myeloid cells rather than acting as an autonomous switch (PMID:9834056, PMID:10741393). High-affinity recognition of CD48 is mediated by the CD244 V domain (notably residues Lys68 and Glu70) and requires N-linked glycosylation, while sialylation and O-linked glycosylation dampen the interaction (PMID:16002700, PMID:21606496). Engagement triggers Src-family kinase-dependent tyrosine phosphorylation of the cytoplasmic ITSMs within actin-dependent lipid rafts, and the signaling outcome is determined by the adaptor balance at these motifs: SAP binding to the ITSMs drives activation via Fyn recruitment, LAT association, and the Ras/Raf/ERK and p38 pathways (with PKC-delta and 3BP2/Vav-1 selectively required for cytotoxicity and p38/transcription for IFN-gamma), whereas SAP paucity allows the third ITSM to recruit SHP-1, SHP-2, SHIP, and Csk and convert the receptor to an inhibitory mode (PMID:11714782, PMID:12515815, PMID:15713798, PMID:16177062, PMID:17599905). The activation-versus-inhibition decision is set by SAP abundance, receptor expression level, degree of cross-linking, isoform identity, ligand-induced internalization, and co-engagement of competing or inhibitory receptors (PMID:17111350, PMID:18523281, PMID:19499526, PMID:17171759). In NK biology CD244–CD48 interactions support IL-2-driven expansion, enforce MHC-independent self-tolerance, and protect NK cells from perforin-dependent fratricide (PMID:15905190, PMID:15870174, PMID:17537992), while in CD8+ T cells CD244 acts as a co-inhibitory receptor revealed under CD28 blockade and chronic infection (PMID:24493803, PMID:26150504). On macrophages and monocytes CD244 functions as a 'don't eat me' receptor that restrains phagocytosis, anti-tumorigenic macrophage differentiation, and antigen presentation by engaging SH2-domain phosphatases that block LRP1-mTOR/Syk signaling and by suppressing autophagy (PMID:35061505, PMID:38424542), and it sustains leukemia-initiating cells through a c-Kit/SHP-2/p27 axis (PMID:28128968).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Establishing that 2B4 is the counter-receptor for CD48 defined the molecular ligand pair underlying all subsequent CD244 signaling.

    Evidence Immunofluorescence and immunoprecipitation with a CD48-Fc chimeric fusion protein

    PMID:9834056

    Open questions at the time
    • Binding affinity and structural basis not yet resolved
    • Functional consequence of engagement not addressed
  2. 2000 High

    Defining 2B4 as a co-receptor that requires co-engagement of triggering receptors (NKp46) and is blocked at the phosphorylation step by inhibitory receptors established that it does not act as an independent activating receptor.

    Evidence Redirected killing assays, antibody co-ligation, and tyrosine phosphorylation assays in NK cells

    PMID:10741393 PMID:11034353

    Open questions at the time
    • Identity of the kinase phosphorylating 2B4 not defined
    • Mechanism by which inhibitory receptors block phosphorylation unclear
  3. 2000 High

    Mapping the downstream cascade to LAT, Ras/Raf/ERK, and p38 with bifurcation between cytotoxicity and IFN-gamma pathways revealed how a single receptor controls distinct effector outputs.

    Evidence Co-IP of 2B4 with LAT, pathway inhibitors, AP-1 DNA binding, and cytotoxicity/IFN-gamma assays

    PMID:10929061 PMID:11163399 PMID:11714782

    Open questions at the time
    • Adaptor linking 2B4 to LAT not identified
    • SAP requirement not yet integrated into the signaling map
  4. 2003 High

    Showing that phosphorylated 2B4 partitions into actin-dependent lipid rafts and that PKC-delta and an AP-1 promoter element regulate function and transcription connected membrane organization and feedback control to receptor signaling.

    Evidence Detergent-resistant membrane fractionation, actin and raft disruption, PKC/PI3K inhibitors, promoter mutagenesis, T-cell isoform transduction

    PMID:12515815 PMID:12734329 PMID:12807490

    Open questions at the time
    • How phosphorylation drives raft entry mechanistically unresolved
    • Relative contributions of cis vs trans CD48 engagement in different cell types unclear
  5. 2005 High

    Dissecting the four ITSMs showed SAP binds all of them while the third ITSM recruits SHP-1/SHP-2/SHIP/Csk, providing the molecular switch between activation and inhibition and explaining 2B4 dysfunction in SAP-deficient XLP.

    Evidence ITSM mutagenesis, in vitro binding, co-IP, and NK assays with XLP patient cells

    PMID:15713798

    Open questions at the time
    • Stoichiometry of SAP versus phosphatase occupancy in vivo not quantified
    • Fyn versus Csk roles in setting outcome not fully separated
  6. 2005 High

    Knockout mouse and structural/mutational studies established CD244-CD48 as an MHC-independent tolerance and fratricide-protection system and defined the V-domain binding interface.

    Evidence 2B4-/-, beta2m-/- and CD48-/- mice, in vivo tumor/bone-marrow rejection, V-domain mutagenesis with CD48-Fc binding, and CD48 crystal structure

    PMID:15634901 PMID:15870174 PMID:15905190 PMID:16002700 PMID:16177062 PMID:16803907

    Open questions at the time
    • Gender-specific CD48-independent defect mechanism unexplained
    • Human relevance of murine tolerance phenotypes not directly tested
  7. 2007 High

    Defining direct Fyn binding and the SAP/EAT-2/PLC-gamma1 interaction network, plus CD2 competition for CD48, clarified how co-engaged receptors and adaptors set CD244 output.

    Evidence Quantitative SH2-domain interaction analysis, co-IP, cytoplasmic motif mutagenesis, and fratricide assays with perforin-deficient mice

    PMID:17537992 PMID:17599905 PMID:19586919

    Open questions at the time
    • In vivo balance between SAP, EAT-2 and phosphatase signaling not quantified
    • Human/mouse divergence in 3BP2 usage not reconciled
  8. 2008 High

    Demonstrating in a controlled system that 2B4 expression level, cross-linking degree, and SAP abundance dictate activation versus inhibition unified prior contradictory observations into a quantitative model.

    Evidence Reconstitution expressing human and murine 2B4 under identical conditions with varied expression and cross-linking, plus SAP-level correlation and isoform comparisons

    PMID:16493031 PMID:17171759 PMID:18523281 PMID:19499526

    Open questions at the time
    • Thresholds defining the switch not absolutely quantified
    • Isoform-specific signaling differences not mechanistically resolved
  9. 2013 Medium

    Identifying ligand-induced and TCR-coupled internalization to an acidic compartment established receptor downmodulation as an additional layer controlling CD244-mediated T-cell function.

    Evidence Src-kinase-dependent internalization assays, pH-sensitive tetramer tracking, and ex vivo HIV-specific CD8 T cells

    PMID:17111350 PMID:23913963

    Open questions at the time
    • Trafficking machinery mediating internalization not identified
    • Fate of internalized receptor (recycling vs degradation) unresolved
  10. 2015 Medium

    Demonstrating microbiota- and gut-environment-induced SLAMF4 that restrains IEL expansion and an lncRNA-CD244/EZH2 axis silencing IFN-gamma/TNF-alpha extended CD244 into mucosal homeostasis and chronic-infection T-cell exhaustion.

    Evidence Slamf4-/- mice, gnotobiotic/chimera models, oral infection, adoptive transfer, and ChIP for H3K27me3 with EZH2 recruitment

    PMID:21622868 PMID:25678452 PMID:26150504 PMID:28341747

    Open questions at the time
    • Direct link between CD244 receptor signaling and lncRNA induction incomplete
    • Bacterial product directly inducing SLAMF4 not identified
  11. 2022 High

    Establishing CD244 as a myeloid 'don't eat me' receptor and a leukemia-initiating-cell dependency expanded its role beyond lymphocytes into phagocytosis control, tumor immunity, and oncogenesis.

    Evidence SFR-deficient and monocyte-lineage conditional CD244-/- mice, phagocytosis/CAR-macrophage assays, scRNA-seq, and co-IP of CD244 with c-Kit and SHP-2

    PMID:28128968 PMID:35061505 PMID:38424542

    Open questions at the time
    • Ligand engaged on macrophages versus phagocytic targets not fully defined
    • Connection between phosphatase-based phagocytosis suppression and autophagy suppression not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the quantitative balance of SAP, EAT-2, Fyn, Csk and SH2-phosphatases is set in distinct cell lineages to convert CD244 from activating to inhibitory in vivo remains unresolved.
  • No unified in vivo measurement of adaptor/phosphatase occupancy across cell types
  • Structural model of the full CD244-CD48-adaptor signaling complex lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 4 GO:0001618 virus receptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
CD48CSKFYNKITLATPTPN11SH2D1ASH3BP2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 2B4 (CD244) was identified as a counter-receptor (ligand) for CD48 by immunofluorescence and immunoprecipitation experiments using a chimeric CD48-IgG1 fusion protein. Immunofluorescence and immunoprecipitation with CD48-Fc chimeric fusion protein Journal of immunology High 9834056
2000 Cross-linking of 2B4 on NK cells results in rapid tyrosine phosphorylation of 2B4; co-ligation of inhibitory receptors KIR2DL1 or CD94/NKG2 completely blocks this tyrosine phosphorylation, placing inhibitory receptor action at or upstream of 2B4 phosphorylation. NK cell activation assays, tyrosine phosphorylation assays, antibody-mediated co-ligation experiments Journal of immunology High 11034353
2000 2B4 functions as a co-receptor in human NK cell activation; activation via 2B4 in redirected killing is strictly dependent upon co-engagement of NKp46, demonstrating that 2B4 requires coligation of triggering receptors rather than acting as an independent activating receptor. Redirected killing assays, mAb-mediated modulation/blocking of NKp46 and 2B4, NK cell clones with varying NKp46 surface density European journal of immunology High 10741393
2000 2B4 signaling in NK cells activates AP-1 DNA binding and involves LAT (linker for activation of T cells), with 2B4 constitutively associating with LAT; downstream signaling activates Ras/Raf, ERK1/2, and p38 pathways for cytotoxicity, while only p38 and transcription are required for IFN-γ release, indicating distinct pathways for these two effector functions. Inhibitor treatment (specific kinase/pathway inhibitors), AP-1 DNA binding assays, co-immunoprecipitation of 2B4 with LAT, NK cell cytotoxicity assays Journal of immunology High 11714782
2000 Interaction of 2B4 on effector NK cells with CD48 on target cells induces NK cell activation (increased cytotoxicity and IFN-γ secretion); SAP is required for this activating function, and co-ligation of NK inhibitory receptors reduces 2B4-mediated activation. NK cell cytotoxicity assays, IFN-γ secretion assays, antibody blocking Molecular immunology Medium 11163399
2000 2B4 stimulation of NK cells (YT cell line) induces natural cytotoxicity, IFN-γ production, downregulation of 2B4 surface expression and mRNA, and upregulation of matrix metalloproteinase-2, suggesting a role for 2B4 signaling in NK cell invasiveness. mAb-mediated 2B4 cross-linking, cytotoxicity assays, IFN-γ ELISA, flow cytometry, RT-PCR, MMP-2 assay Immunology Medium 10929061
2003 After 2B4 engagement (by antibodies or CD48-expressing target cells), phosphorylated 2B4 is found exclusively in detergent-resistant lipid raft fractions; lipid raft integrity is essential for 2B4 phosphorylation and activating function; recruitment of 2B4 into rafts is dependent on actin polymerization; inhibitory receptor co-engagement blocks both 2B4 phosphorylation and raft association. Detergent-resistant membrane fractionation, phosphorylation assays, actin polymerization inhibition, lipid raft disruption, NK cell activation assays Journal of experimental medicine High 12515815
2003 PKC-delta is activated upon 2B4 stimulation; PKC activity is required for 2B4-mediated cytotoxicity but not IFN-γ secretion (which requires PI3K); an AP-1 binding site at position -106 to -100 in the 2B4 promoter is essential for 2B4 transcription and for PMA/PKC-induced upregulation of 2B4. PKC inhibitors, PKC isoform depletion, PI3K inhibitor, AP-1 site mutagenesis, promoter-reporter assays, cytotoxicity assays Immunology Medium 12807490
2003 2B4 augments antigen-specific CD8+ T cell cytotoxicity through trans interaction with CD48 on neighboring T cells (homotypic T cell-T cell interaction), not through ligation of 2B4 by CD48 on target cells; this was shown using 2B4S and 2B4L isoform transduction in primary T cells. Retroviral transduction of 2B4 isoforms into primary T cell cultures, cytotoxicity assays against CD48+ and CD48- targets Journal of immunology Medium 12734329
2005 The first ITSM in the 2B4 cytoplasmic tail is sufficient for NK cell activation; the third ITSM negatively influences 2B4 signaling. SAP binds all four ITSMs in a phosphorylation-dependent manner; the phosphorylated third ITSM additionally recruits SHP-1, SHP-2, SHIP, and Csk. SAP blocks recruitment of these negative regulators to 2B4, explaining why 2B4 inhibits NK cells in XLP (SAP-deficient) patients. Fyn kinase associates with phosphorylated 2B4, and both Fyn and Csk can phosphorylate 2B4. ITSM mutagenesis, in vitro binding assays, co-immunoprecipitation, NK cell activation assays with XLP patient cells Blood High 15713798
2005 Homotypic 2B4/CD48 interactions among NK cells are essential for IL-2-driven NK cell expansion and activation; absence of 2B4/CD48 interaction (using 2B4-deficient or CD48-deficient NK cells) severely impairs NK cytotoxicity, IFN-γ secretion, and calcium signaling; this homotypic interaction was visualized by localization of GFP-tagged 2B4 to NK-NK conjugation sites. 2B4-deficient mouse NK cells, blocking antibodies, calcium signaling assays, GFP-2B4 live imaging of NK-NK conjugation sites, in vivo tumor rejection assays Blood High 15905190
2005 2B4 and MHC class I receptors act non-redundantly to inhibit NK lysis of syngeneic tumor cells; 2B4/CD48 interactions provide a second MHC-independent system for murine NK cell self-tolerance, as demonstrated in beta2m-deficient mice and in vivo bone marrow rejection assays. 2B4-deficient mice, beta2m-deficient mice, in vivo bone marrow rejection assay, in vitro NK lysis assays Blood High 15870174
2005 Targeted deletion of 2B4 in mice reveals that ligation of 2B4 by CD48 on melanoma target cells is inhibitory (wild-type mice rejected CD48- melanoma better than CD48+ melanoma); male 2B4-/- mice showed enhanced rejection of CD48+ melanoma cells; a gender-specific, CD48-independent defect was also identified in female 2B4-/- mice. Gene-targeted 2B4-/- mice, in vivo B16 melanoma rejection assays with CD48+ and CD48- tumor cells Journal of immunology High 15634901
2005 The adaptor protein 3BP2 directly and physically interacts with human CD244 (but not murine CD244) at Tyr337 in a phosphorylation-dependent manner; CD244 ligation induces 3BP2 phosphorylation and Vav-1 recruitment; overexpression of 3BP2 increases ERK activation magnitude and duration after CD244 triggering and enhances cytotoxicity but not IFN-γ secretion. Yeast three-hybrid analysis, co-immunoprecipitation, site-directed mutagenesis (Y337F), Vav-1 recruitment assay, cytotoxicity and IFN-γ assays Journal of immunology High 16177062
2005 Mutational analysis identified Lys68 and Glu70 in the V domain of human 2B4 as critical residues for CD48 binding; double mutant K68A/E70A abrogates CD48 interaction and functional NK cell activation through 2B4. Site-directed mutagenesis of 2B4 V domain, flow cytometry binding assay with soluble CD48-Fc fusion protein, functional NK cell activation assays Journal of immunology High 16002700
2006 2B4 can also function as an activating NK cell ligand: 2B4-expressing target cells stimulate NK cell cytotoxicity and IFN-γ production through interaction with NK cell-expressed CD48 (not through other SLAM receptors on NK cells), adding CD48 to the list of activating NK cell receptors. Soluble receptor fusion proteins, SRR-transfected cells, anti-CD48 blocking antibodies, redirected lysis assay Journal of immunology Medium 16585556
2006 2B4 surface expression is strongly down-modulated and internalized following stimulation by antibody cross-linking or target cell CD48; this modulation is dependent on Src-family kinase activity but independent of PI3K or actin polymerization; inhibitory KIRs do not influence 2B4 modulation; reduced surface 2B4 after ligand-induced internalization results in reduced NK cell activation. Flow cytometry of 2B4 surface levels, specific kinase inhibitors, internalization assays, NK cell cytotoxicity assays European journal of immunology Medium 17111350
2006 Crystal structure of CD48 reveals its receptor-binding surface is unusually flat; CD48 cross-reacts with both CD2 and CD244 (2B4) due to simple arrangement of charged residues and flat topology; thermodynamic analysis shows CD48-CD2 binding is driven by weak equivalent enthalpic and entropic effects. X-ray crystallography, thermodynamic binding analysis Journal of biological chemistry High 16803907
2007 FYN kinase directly interacts with the cytoplasmic region of CD244 in both mouse and human; the SH2 domains of SAP and EAT-2 and FYN kinase all interact with CD244; EAT-2 is not inhibitory per se; the signaling mechanism of CD244 regulates FYN kinase recruitment and/or activity, with outcome determined by which other receptors are co-engaged. Quantitative analysis of direct molecular interactions of SH2 domains with CD244, co-immunoprecipitation, functional NK cell assays Journal of biological chemistry High 17599905
2007 In the absence of 2B4-CD48 interactions (using 2B4-deficient, CD48-deficient mice, or blocking antibodies), activated murine NK cells kill each other (fratricide) in a perforin-dependent manner; 2B4 thus protects NK cells from mutual killing. 2B4-deficient and CD48-deficient mice, blocking antibodies, in vitro and in vivo fratricide assays, perforin-deficient mice Blood High 17537992
2008 Both human and murine 2B4 can activate or inhibit NK cells; the level of 2B4 expression and degree of 2B4 cross-linking regulate SAP-mediated signaling outcome: high 2B4 expression, heavy cross-linking, and relative SAP paucity promote inhibitory function, while low 2B4 expression and SAP abundance promote activation. Controlled model system expressing human and murine 2B4 under identical conditions, varying 2B4 expression levels and cross-linking, NK cell activation assays Journal of immunology High 18523281
2009 CD244 inhibition and activation depend on both CD2 (competing for CD48 at the cell surface) and phospholipase C-gamma1 (recruited via phosphorylated EAT-2); inhibitory effects of mouse CD244 are accounted for by competition with CD2 for CD48; a conserved intracellular link between CD244 and CD2 may occur through FYN kinase. Mutagenesis of CD2 and CD244 cytoplasmic motifs, antigen-specific IL-2 production assays, biochemical interaction studies in mouse T cell hybridoma Journal of biological chemistry Medium 19586919
2009 Two human 2B4 isoforms (h2B4-A and h2B4-B) differ in binding affinity for CD48 due to conformational differences in their extracellular domains; h2B4-A mediates natural cytotoxicity against CD48-expressing targets and induces intracellular calcium release, whereas h2B4-B shows no such effects; 2B4 stimulation decreases mRNA of both isoforms. Isoform-specific functional assays, CD48 binding assays, intracellular calcium measurements, RT-PCR, 3D structural modeling European journal of immunology Medium 19499526
2011 2B4 is heavily and differentially glycosylated in primary human NK cells; N-linked glycosylation of 2B4 is essential for binding to CD48 (demonstrated with recombinant extracellular domain fusion protein); sialylation negatively impacts ligand binding (desialylation increases 2B4-CD48 interaction and 2B4-mediated cytotoxicity); inhibition of O-linked glycosylation also increases 2B4-mediated lysis. Recombinant 2B4 extracellular domain fusion protein, glycosylation inhibitors, enzymatic desialylation, CD48 binding assays, NK cell cytotoxicity assays Journal of biological chemistry High 21606496
2011 Slamf4 (CD244) has an NK cell-independent negative regulatory role in humoral autoimmunity; B6.Slamf4-/- mice spontaneously develop activated CD4 T cells, B cells, increased T follicular helper cells, and autoantibodies; NK depletion studies confirmed the humoral autoimmunity is NK cell-independent. Slamf4-/- knockout mice, NK cell depletion, flow cytometry of T and B cell activation markers, autoantibody measurement, lupus transfer model Journal of immunology High 21622868
2013 CD244 is specifically upregulated on antigen-specific CD8+ T cells when CD28 signaling is blocked (but not during CTLA-4 Ig treatment); this 2B4 upregulation plays a functional inhibitory role, as 2B4-deficient CD8+ T cells are not inhibited by CD28 blockade. In vivo allograft model, CD28 pathway blockade, flow cytometry of CD8 T cells, 2B4-deficient mice Journal of experimental medicine High 24493803
2015 SLAMF4 (CD244) expression on intestinal CD8αβ+ αβTCR+ intraepithelial lymphocytes is induced by the intestinal environment after gut homing; SLAMF4 signaling negatively regulates expansion of cytotoxic CD8αβ+ IELs; Slamf4-/- mice show increased cytotoxic IEL expansion, prolonged depletion of lamina propria CX3CR1+ phagocytes, and enhanced small intestinal inflammation. Slamf4-/- knockout mice, anti-SLAMF4 antibody treatment, adoptive transfer of OT-I cells, anti-CD3 stimulation, live-cell confocal imaging, cytokine and granzyme B assays Gastroenterology High 25678452
2015 SLAMF4 expression on intestinal immune cells is induced directly in the intestinal mucosa by gut bacterial products (particularly anaerobes) and gut-resident antigen-presenting cells, without involvement of gut-associated lymphoid tissue; SLAMF4-deficient mice have increased susceptibility to oral pathogens. Gnotobiotic mice, GFP+ bone marrow chimera mice, lymphotoxin-α and TNLG8A-deficient mice, oral infection with Listeria monocytogenes and Citrobacter rodentium Gut High 28341747
2017 CD244 is highly expressed on mouse and human leukemia initiating cells; CD244 knockdown impairs leukemia cell proliferation in vitro and in vivo, and delays AML leukemogenesis; CD244 is physically associated with c-Kit and SHP-2; CD244 cooperates with c-Kit to activate SHP-2 signaling which dephosphorylates p27 to maintain p27 stability and promote leukemia development. CD244 knockdown in human and mouse leukemia cells, MLL-AF9 murine AML model, co-immunoprecipitation of CD244 with c-Kit and SHP-2, p27 phosphorylation analysis, in vivo leukemia transplantation assays Haematologica High 28128968
2022 SLAMF3 and SLAMF4 (CD244) function as 'don't eat me' receptors on macrophages, inhibiting phagocytosis of hematopoietic cells; these receptors suppress 'eat me' signals (LRP1-mediated mTOR and Syk activation) through SH2 domain-containing phosphatases; SFR deficiency triggers macrophage phagocytosis of hematopoietic cells leading to graft rejection; SFRs act independently of but combined with CD47. SFR-deficient mice, bone marrow transplantation/rejection assays, phagocytosis assays, phosphatase interaction studies, CAR-macrophage assays Science immunology High 35061505
2024 CD244 on monocytes/macrophages restrains anti-tumorigenic macrophage (Ly6Clow) generation, phagocytosis, and MHC-I antigen presentation by suppressing autophagy pathways; ER stress increases CD244 expression on monocytes; monocyte-lineage-specific CD244 deletion (LysMcre) significantly reduces tumor volume and increases tumor-infiltrating anti-tumorigenic macrophages and antigen-specific CD8+ T cells. Monocyte-lineage-specific CD244-/- mice (cre-lox), B16F10 melanoma model, flow cytometry, single-cell RNA sequencing, ex vivo macrophage differentiation and phagocytosis assays, adoptive transfer of CD244-/- macrophages Molecular cancer High 38424542
2013 TCR stimulation combined with simultaneous CD244 engagement causes rapid internalization of CD244 to an acidic intracellular compartment; this two-signal CD244 downmodulation requires both TCR and CD244 signaling and is not induced by PMA-ionomycin or prevented by PI3K inhibition; CD244 internalization correlates with enhanced IFN-γ production upon CD48 blockade in HIV+ subjects. pH-sensitive fluorophore-avidin-antibody tetramers to track CD244 internalization, pharmacological inhibitors, CD8+ T cell clones, ex vivo HIV-specific T cells Journal of immunology Medium 23913963
2006 B cell (particularly marginal zone B cell)-induced NK cell IL-13 mRNA expression requires ligation of CD244 (2B4) on NK cells by CD48 on B cells via direct cell-cell contact; this activation pathway requires SAP expression in NK cells. NK-B cell co-culture, CD244/CD48 blocking, SAP-deficient NK cells, IL-13 mRNA measurement Journal of immunology Medium 16493031
2007 SAP expression in human NK cells is low in resting cells and upregulated by IL-2 stimulation (enhanced by IL-12, TLR3 stimulation); upregulated SAP enables 2B4 alone to stimulate NK cytotoxicity, whereas in resting (low SAP) NK cells 2B4 requires co-triggering with other receptors, demonstrating a direct correlation between SAP expression level and 2B4 activating function. SAP mRNA and protein measurement, IL-2 and cytokine stimulation, NK cell cytotoxicity assays with 2B4 alone or co-triggered European journal of immunology Medium 17171759
2015 CD244 signaling in CD8+ T cells during tuberculosis drives expression of lncRNA-CD244 by sustaining a permissive chromatin state at the lncRNA-CD244 locus; lncRNA-CD244 recruits EZH2 to the ifng/tnfa promoters, mediating H3K27 trimethylation and repressive chromatin states that inhibit IFN-γ and TNF-α expression; lncRNA-CD244 knockdown restores cytokine production. CD244 blockade, lncRNA knockdown, ChIP for H3K27me3, EZH2 recruitment assay, adoptive transfer of lncRNA-CD244-depressed CD8+ T cells to M. tuberculosis-infected mice Proceedings of the National Academy of Sciences Medium 26150504

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Nail polish as a source of exposure to triphenyl phosphate. Environment international 191 26485058
2000 2B4 functions as a co-receptor in human NK cell activation. European journal of immunology 185 10741393
2010 The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatology (Baltimore, Md.) 182 21064032
2015 Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection. Proceedings of the National Academy of Sciences of the United States of America 171 26150504
2005 Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 166 15713798
2009 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clinical cancer research : an official journal of the American Association for Cancer Research 164 19638467
2009 Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease. Journal of the European Academy of Dermatology and Venereology : JEADV 150 19686380
1998 Identification of the 2B4 molecule as a counter-receptor for CD48. Journal of immunology (Baltimore, Md. : 1950) 130 9834056
2008 Molecular basis of the dual functions of 2B4 (CD244). Journal of immunology (Baltimore, Md. : 1950) 122 18523281
2018 The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment. Frontiers in immunology 114 30546369
2001 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunological reviews 109 11513145
2002 Nail-patella syndrome. Overview on clinical and molecular findings. Pediatric nephrology (Berlin, Germany) 102 12215822
2011 Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS pathogens 99 21625589
2003 Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts. The Journal of experimental medicine 99 12515815
2005 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells. Molecular immunology 89 15607804
2005 2B4 (CD244) is expressed and functional on human eosinophils. Journal of immunology (Baltimore, Md. : 1950) 88 15611233
2012 Evolving role of 2B4/CD244 in T and NK cell responses during virus infection. Frontiers in immunology 87 23248626
1997 Cosegregation of open-angle glaucoma and the nail-patella syndrome. American journal of ophthalmology 79 9323941
2005 Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells. Journal of immunology (Baltimore, Md. : 1950) 78 15634901
2001 2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways. Journal of immunology (Baltimore, Md. : 1950) 78 11714782
2000 LMX1B transactivation and expression in nail-patella syndrome. Human molecular genetics 78 10767331
2000 NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). Journal of immunology (Baltimore, Md. : 1950) 78 11034353
2005 Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions. Blood 75 15905190
2000 2B4-mediated activation of human natural killer cells. Molecular immunology 75 11163399
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
2021 Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases. Frontiers in immunology 70 33841431
2008 Kidney disease in nail-patella syndrome. Pediatric nephrology (Berlin, Germany) 67 18535845
1992 Mohs micrographic surgery of the nail unit. The Journal of dermatologic surgery and oncology 67 1644945
2000 2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism. Human immunology 65 10658976
2003 Cutting edge: the NK cell receptor 2B4 augments antigen-specific T cell cytotoxicity through CD48 ligation on neighboring T cells. Journal of immunology (Baltimore, Md. : 1950) 64 12734329
2012 Nail psoriasis: a review. American journal of clinical dermatology 63 22784035
2020 Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer. Cancers 62 32630303
2014 2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses. The Journal of experimental medicine 60 24493803
2010 Pigmented lesions of the nail unit: clinical and histopathologic features. Seminars in cutaneous medicine and surgery 60 21051008
2022 SLAMF3 and SLAMF4 are immune checkpoints that constrain macrophage phagocytosis of hematopoietic tumors. Science immunology 58 35061505
2010 Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus. Clinical and experimental immunology 57 20345977
2006 CD48 stimulation by 2B4 (CD244)-expressing targets activates human NK cells. Journal of immunology (Baltimore, Md. : 1950) 51 16585556
2020 CD244 represents a new therapeutic target in head and neck squamous cell carcinoma. Journal for immunotherapy of cancer 49 32217758
2014 Characteristics of patients with yellow nail syndrome and pleural effusion. Respirology (Carlton, Vic.) 48 25123563
2006 2B4 (CD244), NTB-A and CRACC (CS1) stimulate cytotoxicity but no proliferation in human NK cells. International immunology 47 16410313
2001 Overexpression and purification of the membrane-bound cytochrome P450 2B4. Protein expression and purification 47 11237692
2019 KDM4B: A Nail for Every Hammer? Genes 46 30759871
2013 Drug-related nail disease. Clinics in dermatology 46 24079591
2011 DNA from keratinous tissue. Part I: hair and nail. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 46 21530205
2006 Regulation of 2B4 (CD244)-mediated NK cell activation by ligand-induced receptor modulation. European journal of immunology 45 17111350
2000 2B4 stimulation of YT cells induces natural killer cell cytolytic function and invasiveness. Immunology 45 10929061
2013 Nail tumors. Clinics in dermatology 42 24079590
2005 2B4 (CD244)-CD48 interactions provide a novel MHC class I-independent system for NK-cell self-tolerance in mice. Blood 42 15870174
2005 The adaptor protein 3BP2 binds human CD244 and links this receptor to Vav signaling, ERK activation, and NK cell killing. Journal of immunology (Baltimore, Md. : 1950) 42 16177062
2011 Glycosylation affects ligand binding and function of the activating natural killer cell receptor 2B4 (CD244) protein. The Journal of biological chemistry 41 21606496
2006 The co-expression of 2B4 (CD244) and CD160 delineates a subpopulation of human CD8+ T cells with a potent CD160-mediated cytolytic effector function. European journal of immunology 41 16917959
2008 Regulation of NK cell activity by 2B4, NTB-A and CRACC. Frontiers in bioscience : a journal and virtual library 40 17981603
2003 In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys. The American journal of pathology 38 12819019
2017 Important malignant and new nail tumors. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 37 28378483
2009 2B4 (CD244) signaling via chimeric receptors costimulates tumor-antigen specific proliferation and in vitro expansion of human T cells. Cancer immunology, immunotherapy : CII 37 19360406
2013 Identification of CD244-expressing myeloid-derived suppressor cells in patients with active tuberculosis. Immunology letters 35 24333340
2012 Evaluation of nail abnormalities. American family physician 34 22534387
2011 Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 34 21622868
2005 2B4/CD48-mediated regulation of lymphocyte activation and function. Journal of immunology (Baltimore, Md. : 1950) 34 16081768
2018 Squamous cell carcinoma of the nail unit. Dermatology practical & conceptual 33 30116671
2007 Modulation of 2B4 (CD244) activity and regulated SAP expression in human NK cells. European journal of immunology 33 17171759
2017 CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1 signaling. Haematologica 32 28126968
2015 Elevated Expression of CD160 and 2B4 Defines a Cytolytic HIV-Specific CD8+ T-Cell Population in Elite Controllers. The Journal of infectious diseases 32 25883386
2013 Tumors of the nail unit. A review. Part II: acquired localized longitudinal pachyonychia and masked nail tumors. The American Journal of dermatopathology 31 24056180
2009 Functional role of human NK cell receptor 2B4 (CD244) isoforms. European journal of immunology 31 19499526
2006 Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells. Immunology letters 31 16621032
1995 Linkage analysis of the nail-patella syndrome. American journal of human genetics 31 7825584
2017 Nail-patella syndrome. Pflugers Archiv : European journal of physiology 30 28681095
2016 Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis. Arthritis research & therapy 30 27039301
1980 Nail-patella syndrome. Clinical nephrology 30 7418282
2017 Nail tic disorders: Manifestations, pathogenesis and management. Indian journal of dermatology, venereology and leprology 29 27320768
2003 Protein kinase C is involved in 2B4 (CD244)-mediated cytotoxicity and AP-1 activation in natural killer cells. Immunology 29 12807490
2006 Crystal structure and binding properties of the CD2 and CD244 (2B4)-binding protein, CD48. The Journal of biological chemistry 28 16803907
2022 PRAME expression in melanocytic lesions of the nail. Journal of cutaneous pathology 27 35294053
2006 Common nail tumors. Dermatologic clinics 26 16798427
2005 2B4 co-stimulation: NK cells and their control of adaptive immune responses. Molecular immunology 26 15607793
2017 Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens. Gut 25 28341747
2015 CD244 is expressed on dendritic cells and regulates their functions. Immunology and cell biology 25 25643613
2014 Complex 2B4 regulation of mast cells and eosinophils in murine allergic inflammation. The Journal of investigative dermatology 25 24999594
2009 Inhibition and activation by CD244 depends on CD2 and phospholipase C-gamma1. The Journal of biological chemistry 25 19586919
2009 High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease. PLoS pathogens 25 19997502
2007 Autoimmune disorders: nail signs and therapeutic approaches. Dermatologic therapy 25 17403257
2006 B cell induction of IL-13 expression in NK cells: role of CD244 and SLAM-associated protein. Journal of immunology (Baltimore, Md. : 1950) 25 16493031
2021 Single-cell RNA sequencing of human nail unit defines RSPO4 onychofibroblasts and SPINK6 nail epithelium. Communications biology 24 34099859
2021 Quantification of Modified Nucleosides in the Context of NAIL-MS. Methods in molecular biology (Clifton, N.J.) 23 34085252
2003 Induction of hard keratin expression in non-nail-matrical keratinocytes by nail-matrical fibroblasts through epithelial-mesenchymal interactions. Plastic and reconstructive surgery 23 12496590
2018 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer. Clinical immunology (Orlando, Fla.) 22 30347240
2013 Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis. PloS one 22 23638187
2007 Direct and indirect interactions of the cytoplasmic region of CD244 (2B4) in mice and humans with FYN kinase. The Journal of biological chemistry 22 17599905
2005 Mutational analysis of the human 2B4 (CD244)/CD48 interaction: Lys68 and Glu70 in the V domain of 2B4 are critical for CD48 binding and functional activation of NK cells. Journal of immunology (Baltimore, Md. : 1950) 22 16002700
2020 Increasing Tim-3+CD244+, Tim-3+CD57+, and Tim-3+PD-1+ T cells in patients with acute myeloid leukemia. Asia-Pacific journal of clinical oncology 21 32030888
2013 Simultaneous TCR and CD244 signals induce dynamic downmodulation of CD244 on human antiviral T cells. Journal of immunology (Baltimore, Md. : 1950) 21 23913963
2007 2B4 inhibits NK-cell fratricide. Blood 21 17537992
2005 Genetic hair and nail disorders. Clinics in dermatology 21 15708289
2005 P450 active site architecture and reversibility: inactivation of cytochromes P450 2B4 and 2B4 T302A by tert-butyl acetylenes. Biochemistry 21 15751959
2024 TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells. Frontiers in immunology 20 38510235
2021 Increased TOX expression concurrent with PD-1, Tim-3, and CD244 expression in T cells from patients with acute myeloid leukemia. Cytometry. Part B, Clinical cytometry 19 34913594
2015 SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 19 25678452
2024 Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma. Molecular cancer 18 38424542
2018 Surpassing limits of static RNA modification analysis with dynamic NAIL-MS. Methods (San Diego, Calif.) 18 30395967

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