Affinage

CD58

Lymphocyte function-associated antigen 3 · UniProt P19256

Length
250 aa
Mass
28.1 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD58 (LFA-3) is an immunoglobulin superfamily glycoprotein that serves as the principal ligand for CD2 on T cells and NK cells, mediating intercellular adhesion, immunological synapse formation, and costimulatory signaling essential for adaptive and innate immune responses (PMID:2951597, PMID:6984191, PMID:12496412). CD58 exists as GPI-anchored and transmembrane isoforms, with the GPI form exhibiting enhanced lateral mobility that accelerates adhesion strengthening; the CD2–CD58 interaction is driven by charge complementarity between the AGFCC′C″ beta-sheet faces of both proteins, centered on a hot spot involving CD2 Tyr86 and CD58 Lys34 (PMID:3313053, PMID:10200255, PMID:11575926). Engagement of CD58 costimulates T cell activation through NF-AT induction, lipid raft aggregation, and TCR signal amplification, promotes IL-12 responsiveness, drives IgE class switching on B cells, and triggers monokine release from monocytes and epithelial cells (PMID:9032258, PMID:11591762, PMID:8757306, PMID:7515920, PMID:1697984). CD58 protein stability is regulated by CMTM6-mediated endosomal recycling in competition with PD-L1, its transcription is activated by PAX5 and repressed by EZH2-catalyzed H3K27 trimethylation, and loss of CD58—occurring in ~21% of DLBCLs—promotes immune evasion through impaired synapse formation and upregulation of PD-L1/IDO via derepressed JAK2/STAT1 signaling (PMID:37327789, PMID:36516256, PMID:31962268, PMID:22137796, PMID:38635903).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1982 High

    Identification of LFA-3 (CD58) as a target-cell surface molecule required for CTL-mediated killing established its fundamental role in immune cell–cell interaction, answering whether a distinct non-MHC target-cell antigen participates in cytolysis.

    Evidence Monoclonal antibody blocking of CTL killing (51Cr-release), immunoprecipitation, and flow cytometry on B and T lymphocytes

    PMID:6345670 PMID:6984191

    Open questions at the time
    • Identity of the counter-receptor on effector cells unknown
    • Molecular nature of LFA-3 undefined
    • Mechanism of action (adhesion vs. signaling) unresolved
  2. 1984 High

    Demonstration that anti-LFA-3 antibodies block CTL–target conjugate formation resolved that LFA-3 functions at the adhesion step rather than a post-adhesion lytic step.

    Evidence CTL–target conjugate formation assay with mAb blocking

    PMID:6201533

    Open questions at the time
    • Counter-receptor identity still unknown
    • Contribution of LFA-3 to non-CTL immune interactions untested
  3. 1987 High

    Identification of CD2 as the direct receptor for CD58 using purified proteins, and molecular cloning revealing CD58 as an Ig superfamily member with both GPI-anchored and transmembrane isoforms, established the molecular framework for the CD2–CD58 adhesion system.

    Evidence Radiolabeled purified CD2 binding to erythrocyte LFA-3, cDNA cloning with sequence analysis, PIPLC enzymatic treatment distinguishing two anchor forms, reconstitution of purified LFA-3 into PNH erythrocytes restoring rosetting

    PMID:2951597 PMID:3309123 PMID:3313052 PMID:3313053

    Open questions at the time
    • Structural basis of CD2–CD58 interaction unknown
    • Functional significance of two isoforms unclear
    • Signaling consequences of engagement undefined
  4. 1988 High

    Demonstration that LFA-3 engagement of CD2 triggers calcium flux, phosphatidylinositol hydrolysis, and T cell proliferation—requiring an intact CD3/TCR complex—established CD58 as a bona fide costimulatory molecule rather than a simple adhesion factor.

    Evidence Signaling assays in Jurkat cells and CD3-deficient mutants with reconstitution; L cell transfectants driving T cell proliferation blocked by anti-CD2/anti-LFA-3 mAbs

    PMID:2459194 PMID:2834437

    Open questions at the time
    • Downstream transcription factor targets uncharacterized
    • Whether CD58 itself transduces signals (reverse signaling) unknown
  5. 1990 High

    Discovery that CD2 engagement of LFA-3 on monocytes and thymic epithelial cells triggers TNF-α, IL-1α, and IL-1β release established bidirectional signaling through the CD2–CD58 axis—CD58 is not merely a passive ligand.

    Evidence Cytokine release assays with immobilized anti-LFA-3 and purified CD2 on monocytes; monovalent Fab′ fragment stimulation of thymic epithelial cells with actinomycin D/cycloheximide controls

    PMID:1693636 PMID:1697984

    Open questions at the time
    • CD58 reverse signaling pathway components undefined
    • Whether GPI-anchored isoform can signal remains unresolved
  6. 1991 High

    Reconstitution of GPI-anchored versus transmembrane CD58 in planar bilayers showed that the GPI isoform's greater lateral mobility accelerates adhesion strengthening, providing a functional rationale for the two isoforms.

    Evidence Planar phospholipid bilayer reconstitution with purified isoforms, static and laminar flow adhesion assays

    PMID:1717480

    Open questions at the time
    • In vivo relevance of isoform-specific adhesion kinetics untested
    • Regulation of isoform expression across tissues unknown
  7. 1993 High

    NMR-guided and structure-based mutagenesis of both CD2 and CD58 mapped the binding interface to the AGFCC′C″ beta-sheet face of each domain, identifying key charged residues and establishing the electrostatic nature of the interaction.

    Evidence Site-directed mutagenesis guided by NMR structure of CD2, functional rosetting and binding assays for CD2 and CD58 mutants

    PMID:7505442 PMID:7688025

    Open questions at the time
    • No co-crystal structure yet
    • Energetic contribution of individual residues not quantified
  8. 1994 High

    Mapping the CD58-side interface and demonstrating that CD58 ligation on B cells induces IL-4-dependent IgE class switching (distinct from CD40 pathway) broadened CD58's role beyond T cell adhesion to include B cell isotype regulation.

    Evidence CD58 mutagenesis with CD2-binding assays; purified B cell cultures with anti-CD58 mAb or CD2-transfected hybridomas, epsilon transcript analysis

    PMID:7515920 PMID:7525842

    Open questions at the time
    • Signaling pathway from CD58 to epsilon germline transcription unknown
    • In vivo relevance of CD58-driven IgE switching unconfirmed
  9. 1996 High

    Direct visualization of CD58 accumulation at T cell contact sites and measurement of a 2D Kd (~21 molecules/μm²) well below physiological densities, combined with the finding that CD58 optimizes T cell IL-12 responsiveness, established the biophysical basis for efficient synapse-like contact formation.

    Evidence Fluorescence microscopy of planar bilayers with fluorescent LFA-3; CHO transfectants expressing CD58 vs. CD48 in APC-depleted T cell IL-12 response assays

    PMID:8636222 PMID:8757306

    Open questions at the time
    • True immunological synapse architecture with CD58 not yet characterized
    • Whether CD58 segregates into distinct synapse zones unknown
  10. 1999 High

    The 1.8 Å crystal structure of the CD58 adhesion domain confirmed the V-set Ig topology and revealed that charge complementarity rather than shape matching drives CD2 binding specificity, resolving the structural basis of the interaction.

    Evidence X-ray crystallography of chimeric CD58 with mutation mapping

    PMID:10200255

    Open questions at the time
    • Co-crystal of the CD2–CD58 complex not yet solved
    • How charge complementarity translates to fast kinetics not mechanistically explained
  11. 2001 High

    Identification of the CD2 Tyr86–CD58 Lys34 hot spot by ITC of alanine mutants quantified the energetic architecture of the interface and showed that CD58 costimulation promotes lipid raft aggregation as a mechanism of TCR signal amplification.

    Evidence Isothermal titration calorimetry of single-residue CD2 mutants; luciferase reporter assays for AP-1/NF-AT/NF-κB with lipid raft aggregation measurement on endothelial cell costimulation

    PMID:11575926 PMID:11591762

    Open questions at the time
    • Raft aggregation mechanism downstream of CD2 undefined
    • Whether raft mechanism applies in vivo during APC encounter unknown
  12. 2011 High

    Discovery that CD58 is genetically inactivated (mutations/deletions) in 21% of DLBCLs, co-occurring with β2-microglobulin loss, established CD58 as a tumor suppressor whose loss enables dual escape from T and NK cell surveillance.

    Evidence Sequencing and deletion analysis of CD58 in primary DLBCL samples, flow cytometry for surface expression, correlation with HLA-I loss

    PMID:22137796

    Open questions at the time
    • Functional immune evasion not directly demonstrated in these tumors
    • Whether CD58 loss is a driver or passenger event unresolved
  13. 2015 High

    Establishing CD58–CD2 as the primary costimulatory pathway for CD28-negative CD8+ T cells explained how terminally differentiated effector cells maintain responsiveness in the absence of classical costimulation.

    Evidence mAb blocking of CD58 in DC-stimulated CD28⁻CD8⁺ T cell assays measuring proliferation, cytokines, and responses to viral antigens

    PMID:26041540

    Open questions at the time
    • Molecular basis for CD58 dominance over other CD2 ligands (CD48, CD59) in this context unexplored
    • In vivo validation lacking
  14. 2020 High

    Demonstration that EZH2 silences CD58 via H3K27me3 at its promoter, and that CD58 knockout disrupts T cell rosetting in Hodgkin lymphoma requiring both CD58-CD2 and TCR-HLA-II interactions, linked epigenetic regulation to immunological synapse integrity.

    Evidence ChIP for H3K27me3 at CD58 promoter with EZH2 inhibitor rescue; CRISPR KO of CD58 in HL cell lines with rosetting and proximity ligation in primary tissue

    PMID:31962268 PMID:32589698

    Open questions at the time
    • Whether EZH2-mediated silencing is specific to lymphoma or occurs broadly untested
    • Precise structure of CD58-dependent immunological synapse undefined
  15. 2022 High

    Genome-wide CRISPR screens identified CD58 as a top resistance gene for CAR T cell therapy and PAX5 as a transcriptional activator of CD58 via an enhancer element, mechanistically connecting transcription factor mutations to immune evasion.

    Evidence CRISPR screens for CAR T cell and blinatumomab sensitivity; CD58 KO with IS imaging and functional validation; PAX5 P80R genome editing with ChIP/ATAC-seq for enhancer characterization

    PMID:35728062 PMID:36516256

    Open questions at the time
    • Whether restoring CD58 expression rescues CAR T resistance in vivo untested
    • Full catalog of transcription factors regulating CD58 incomplete
  16. 2023 High

    Discovery that CMTM6 stabilizes CD58 through endosomal recycling, and that CD58 and PD-L1 compete for CMTM6 binding, revealed a post-translational regulatory axis linking loss of one immune molecule to gain of another inhibitory checkpoint.

    Evidence CRISPR screens, proteomics, co-IP of CD58/PD-L1 with CMTM6, endosomal recycling and lysosomal degradation assays, humanized mouse models, patient melanoma scRNA-seq

    PMID:37327789

    Open questions at the time
    • Structural basis of CMTM6 selectivity between CD58 and PD-L1 unknown
    • Whether CMTM6 competition is therapeutically targetable untested
    • Stoichiometry of the CD58–CMTM6 complex undefined
  17. 2024 Medium

    Identification of the LYN/CD22/SHP1 axis as CD58's mechanism for suppressing JAK2/STAT1 signaling—and showing that CD58 loss derepresses PD-L1 and IDO expression—provided a signaling pathway linking CD58 to immune checkpoint regulation beyond simple adhesion.

    Evidence Co-IP, RNA-seq, whole-exome sequencing, scRNA-seq in DLBCL patient samples, CAR T cell co-culture with pathway inhibitors

    PMID:38635903

    Open questions at the time
    • LYN/CD22/SHP1 pathway downstream of CD58 established in single study
    • Whether this signaling axis operates in non-lymphoma contexts untested
    • Direct physical interaction between CD58 and LYN not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the CD2–CD58 complex, the structural basis for CMTM6 selectivity between CD58 and PD-L1, whether therapeutic restoration of CD58 expression can overcome immune evasion in vivo, and the full signaling cascade downstream of CD58 reverse signaling in non-lymphoid cells.
  • No CD2–CD58 co-crystal structure
  • CD58 reverse signaling pathway largely undefined
  • Therapeutic strategies to restore CD58 not clinically validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098631 cell adhesion mediator activity 6
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1500931 Cell-Cell communication 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 GO:0005576 extracellular region 1
Partners
ALKBH5CD2CD59CMTM6EZH2LYNPAX5

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1982 LFA-3 (CD58) is a cell surface antigen (Mr ~60,000) expressed on both B and T lymphocytes that participates in CTL-target cell interaction; monoclonal antibodies blocking LFA-3 inhibit CTL-mediated killing, with anti-LFA-3 antibodies acting on target cells rather than effectors. Monoclonal antibody inhibition of CTL killing assay (51Cr-release), immunoprecipitation, NaDodSO4/PAGE, immunofluorescence flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 6984191
1983 LFA-3 is a widely distributed antigen (Mr 60,000) present on both hematopoietic and nonhematopoietic tissues that functions on target cells to mediate CTL-mediated cytotoxicity and T cell proliferative responses; anti-LFA-3 MAb block by binding to target cells, not effectors. Monoclonal antibody blocking of CTL killing, MLR, and PHA proliferation assays Journal of immunology High 6345670
1984 LFA-3 mediates CTL-target cell conjugate formation; antibodies to LFA-3 inhibit cytolysis by blocking CTL-target cell adhesion. CTL-target conjugate formation assay, 51Cr-release cytotoxicity assay with monoclonal antibody blocking Journal of immunology High 6201533
1987 LFA-3 (CD58) is the direct cell-surface ligand for CD2; purified CD2 binds to human erythrocyte LFA-3 and mediates adhesion, and purified CD2 inhibits T cell rosetting with erythrocytes in an LFA-3-dependent manner. Radiolabeled (125I) CD2 binding to erythrocytes, rosetting inhibition assay, purified protein binding assays Nature High 2951597
1987 LFA-3 cDNA encodes a phospholipid-linked (GPI-anchored) membrane protein whose extracellular domain shares significant homology with its receptor CD2, both being members of the immunoglobulin superfamily. cDNA cloning, sequence analysis, transient expression in mouse cells Nature High 3313052
1987 LFA-3 exists in two distinct membrane-anchored forms derived from different biosynthetic precursors: one anchored by a phosphatidylinositol glycan (GPI) moiety and one with a conventional transmembrane segment. Phosphatidylinositol-specific phospholipase C (PIPLC) treatment, biosynthetic labeling, biochemical fractionation Nature High 3313053
1987 LFA-3 on erythrocytes is attached to the membrane by a phosphatidylinositol glycolipid anchor; deficiency of LFA-3 on PNH erythrocytes correlates with phosphatidylinositol-anchored protein deficiency, and reconstitution of purified LFA-3 into PNH erythrocytes restores CD2 binding and rosetting activity. PIPLC treatment, 125I-CD2 binding, rosetting assay, reconstitution of purified protein into erythrocyte membranes The Journal of experimental medicine High 3309123
1987 CD2 and LFA-3 mediate thymocyte binding to thymic epithelial cells; anti-LFA-3 antibodies block binding when applied to thymic epithelial cells, while anti-CD2 antibodies block when applied to thymocytes, demonstrating LFA-3 on TE cells engages CD2 on thymocytes. Rosette formation inhibition assay with monoclonal antibodies, indirect immunofluorescence Journal of immunology High 3098838
1987 LFA-3 expressed on human erythrocytes is the ligand for CD2; purified CD2 binds to erythrocyte LFA-3 and mediates T cell rosetting, with LFA-3 mAb blocking 125I-CD2 binding and CD2 blocking LFA-3 mAb binding (reciprocal competition). 125I-CD2 binding competition, mAb blocking of rosetting, purified protein binding The Journal of experimental medicine High 3102675
1988 LFA-3 can activate T cells via the CD2 complex; purified multimeric LFA-3 combined with anti-CD2 mAb induces intracellular calcium increases, phosphatidylinositol second messenger generation, and lymphokine secretion in Jurkat cells, but only when CD3/Ti complex is expressed and functionally intact. Intracellular calcium measurement, phosphatidylinositol hydrolysis assay, lymphokine secretion, CD3-deficient Jurkat mutants with TCR beta-chain reconstitution Journal of immunology High 2459194
1988 LFA-3 expressed on transfected L cells costimulates T cell and thymocyte proliferation via CD2; proliferation is inhibited by anti-CD2 or anti-LFA-3 mAbs and is associated with increased IL-2R expression. L cell transfection with LFA-3 genomic DNA, T cell proliferation assay, mAb blocking, IL-2R expression analysis Journal of immunology High 2834437
1990 Engagement of monocyte LFA-3 by immobilized anti-LFA-3 antibody or by purified CD2 (its physiologic receptor) triggers TNF-alpha and IL-1 beta release from monocytes, demonstrating that the CD2-LFA-3 receptor-ligand adhesion interaction can transmit signals inducing monokine secretion. Cytokine release assay (TNF-alpha, IL-1 beta) with immobilized antibodies and purified CD2 protein Science High 1697984
1990 Binding of anti-LFA-3 mAb (monovalent Fab' fragments sufficient) to thymic epithelial cell LFA-3 augments IL-1 alpha and IL-1 beta mRNA production and protein release, requiring new protein and RNA synthesis; this signals via LFA-3 engagement during thymocyte-TE cell contact. IL-1 release assay, Northern blot, cycloheximide/actinomycin D inhibition, Fab' fragment binding Journal of immunology High 1693636
1991 Lateral mobility of GPI-anchored LFA-3 in the membrane enhances the rate of CD2-mediated cell adhesion strengthening compared to immobile transmembrane LFA-3; the GPI isoform supports more efficient adhesion at lower densities due to its ability to diffuse laterally and accumulate at the contact zone. Planar phospholipid bilayer reconstitution with GPI vs. transmembrane LFA-3 isoforms, static and laminar flow adhesion assays The Journal of cell biology High 1717480
1992 CD59, in addition to CD58, is a physiological ligand for CD2; CD59 binds CD2 at an overlapping but nonidentical binding site to CD58 on CD2, and antibodies to CD59 inhibit CD2-dependent T cell activation. In vitro binding assay with purified CD58 and CD59, CD2+ cell binding, T cell activation in murine hybridomas expressing human CD2, competition binding Science High 1377404
1992 CD58 and CD59 molecules act synergistically (additively or synergistically) in mediating T cell adhesion and costimulating T cell activation; double transfectants expressing both CD58 and CD59 on CHO cells produce far more rosettes and T cell proliferation than either alone. CHO cell transfection with CD58 and/or CD59, rosette formation assay, T cell proliferation assay Journal of immunology Medium 1370512
1993 TCR stimulation or PMA treatment rapidly up-regulates CD2 avidity for CD58, requiring protein tyrosine kinase and protein kinase C activity, as well as the carboxyl-terminal asparagine of the CD2 cytoplasmic domain; cAMP elevation also up-regulates CD2 avidity through the same structural element. CD2+ cells binding to purified CD58, SRBC rosetting assay, inhibitors of PTK and PKC, CD2 cytoplasmic domain mutants Journal of immunology High 7681075
1993 The CD58-binding site on CD2 is a charged surface area (~770 Å2) on the AGFCC'C" face of the CD2 adhesion domain, involving residues on the F strand (Lys-82, Tyr-86), C strand (Asp-32, Lys-34), C' strand (Gln-46), FG loop, CC' loop, and C'C" loop, as identified by NMR-guided site-directed mutagenesis. Site-directed mutagenesis combined with NMR structural data, CD58 binding functional assays Proceedings of the National Academy of Sciences of the United States of America High 7505442
1993 The CD58 binding site on CD2 maps to the beta-sheet containing strands CC'C"FG; key residues K34, E36 (C strand), R48, K49 (C' strand), K91, N92 (FG loop) are critical for CD2 interaction with both human and sheep CD58. Site-directed mutagenesis of CD2 domain 1 based on rat CD2 NMR solution structure, rosetting assay with human and sheep erythrocytes The Journal of experimental medicine High 7688025
1994 The CD58-binding surface on CD2 maps to the major beta-sheet face of CD58 (AGFCC'C" sheet), involving residues on C strand (E25, K29, K30), CC' loop (K32, D33, K34), C' strand (E37), and G strand (K87); the interaction between CD2 and CD58 involves the major beta-sheet face of each adhesion domain. Site-directed mutagenesis of charged residues on CD58 predicted to be solvent-exposed, CD2 binding functional assays The Journal of experimental medicine High 7525842
1994 Ligation of B cell CD58 by CD2 (its natural T cell ligand) or by mAb provides an IL-4-dependent signal for IgE class switching and production, specifically inducing productive epsilon transcripts and IgE production in a pathway distinct from CD40-mediated isotype switching. Highly purified B cell cultures, IL-4 + anti-CD58 mAb, CD2-transfected murine T hybridoma coculture, CD40 Fc fusion protein competition, epsilon germ-line and productive transcript analysis Journal of immunology High 7515920
1996 CD2-CD58 interaction visualized directly in the contact area between T lymphoblasts and planar bilayers containing fluorescently labeled LFA-3; LFA-3 accumulates at sites of contact with half-time ~15 min; the 2D Kd for CD2/LFA-3 interaction is ~21 molecules/μm², well below physiological densities of both molecules. Fluorescence microscopy of planar phospholipid bilayers with purified fluorescent LFA-3, two-dimensional affinity measurement, lateral diffusion analysis The Journal of cell biology High 8636222
1996 CD2-CD58 interaction optimizes T cell response to IL-12; monocyte CD58 engages T cell CD2, and CHO transfectants expressing CD58 at levels comparable to monocytes (but not CD48, a lower-avidity CD2 ligand) restore IL-12 responsiveness to APC-depleted T cells. CHO transfectants expressing CD58 or CD48, APC-depleted T cell cultures, IL-12 response assay, blocking antibodies Journal of immunology High 8757306
1997 CD58 (LFA-3) costimulation via CD2 preferentially induces NF-AT nuclear factor binding and IFN-gamma production in T cells; the NF-AT induced by LFA-3 is negatively regulated by B7-1 costimulation, revealing distinct transcriptional pathways for CD2-LFA-3 vs. CD28-B7-1 costimulation. Gel shift assays for NF-AT, AP-1, NF-kappaB; IL-2 promoter-luciferase reporter transfection; CHO transfectants with HLA-DR, B7-1, and/or LFA-3 Molecular and cellular biology High 9032258
1997 CD2-CD58 bond dynamics in contact areas are transient; fluorescence photobleaching recovery demonstrates rapid dissociation and partner exchange of CD2-CD58 bonds in the contact zone, consistent with the fast solution off-rate (>5 s-1). Fluorescence photobleaching recovery (FRAP) in T cell-planar bilayer contact zones with fluorescent CD58 The Journal of biological chemistry High 9188475
1999 Crystal structure of the CD2-binding domain of CD58 at 1.8 Å resolution reveals an Ig superfamily V-set topology sharing structural features with CD2; the highly acidic AGFCC'C" beta-sheet surface of CD58 is the CD2-binding interface; charge complementarity rather than shape matching drives specificity. X-ray crystallography at 1.8 Å resolution of chimeric CD58, mutation mapping Proceedings of the National Academy of Sciences of the United States of America High 10200255
1999 CD58 is constitutively expressed on the basolateral surface of intestinal epithelial cells (polarized expression) and functions as a costimulatory molecule for CD4+ T cell proliferation mediated by intestinal epithelial cells; CD58 blockade inhibits this costimulation, while CD80 and CD86 are absent. Flow cytometry, confocal microscopy, vectorial biotinylation, antibody blocking of T cell proliferation by IEC lines Gastroenterology High 10220497
2001 CD2 Tyr86 and CD58 Lys34 form the functional hot spot of the CD2-CD58 adhesion interface; Y86A mutation reduces CD58 binding affinity ~1000-fold while Y86F has virtually no effect (hydroxyl not required), and the CD2 D31/D32 residues orient CD58 K34 for hydrophobic contact with CD2 Y86. Isothermal titration calorimetry (ITC) of CD2 alanine mutants, CD2-CD58 crystal structure analysis Journal of molecular biology High 11575926
2001 Endothelial cell costimulation of T cell activation via CD58-CD2 promotes lipid raft aggregation in T cells; CD2 crosslinking promotes raft aggregation and amplifies multiple TCR downstream pathways (AP-1, NF-AT, NF-kappaB) without targeting a single distinct pathway. AP-1/NF-AT/NF-kappaB luciferase reporter assays, IL-2 secretion assay, lipid raft aggregation assay with CD2 mAb blocking Journal of immunology Medium 11591762
2003 Coexpression of CD58 (or CD48) with ICAM-1 on target cells enables strong adhesion of resting NK cells even without cytokine activation; CD58 on targets engages receptors on resting NK cells to strengthen LFA-1-mediated adhesion. Drosophila cell expression system with defined ligand combinations, resting NK cell adhesion assays, inhibitors of src-family kinase and PI3K Journal of immunology High 12496412
2006 T cell activation increases CD2 cell surface number 1.5-fold and 2D affinity for CD58 by 2.5-fold; ligation of CD2 to CD58 decreases lateral mobility of CD2 (likely via cytoskeletal immobilization), collectively enhancing avidity and T cell-APC adhesion. Quantitative CD2 site measurements, 2D affinity measurement in contact zones, lateral mobility (FRAP) of CD2 on activated T cells ACS chemical biology High 17168569
2009 The protective rs2300747(G) allele in the CD58 locus is associated with a dose-dependent increase in CD58 mRNA expression and enhanced function of CD4+CD25high regulatory T cells via FoxP3 upregulation, suggesting CD58 engagement of CD2 promotes Treg function. Fine mapping and resequencing, mRNA expression quantification in LCL and PBMCs, FoxP3 expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 19237575
2011 Mutations and deletions inactivate the CD58 gene in 21% of DLBCL cases, abolishing cell-surface CD58 expression; CD58 genetic inactivation co-occurs with beta2-microglobulin inactivation, enabling escape from both T cell and NK cell immune surveillance. Sequencing of CD58 gene, deletion analysis, flow cytometry for protein expression, correlation with HLA-I loss Cancer cell High 22137796
2016 CD2-CD58 interactions are required for activation of adaptive NKG2C+CD57+ NK cells in response to HCMV-infected fibroblasts; antibody blockade of CD2 or CD58 largely abolishes CD69/CD25/HLA-DR upregulation and IFN-gamma/TNF-alpha production specifically in adaptive NK cells, correlating with HCMV-induced upregulation of CD58 on infected cells. Co-culture of PBMCs with productively infected fibroblasts, blocking antibodies against CD2 and CD58, flow cytometry for activation markers, intracellular cytokine staining European journal of immunology High 27469079
2020 EZH2 epigenetically silences CD58 expression in B-cell lymphoma via H3K27 trimethylation of the CD58 promoter; EZH2 inhibitors (EPZ6438, GSK126) relieve this repression, restore CD58 surface expression, and enhance T and NK cell IFN-gamma production against lymphoma cells. Epigenetic library screening, EZH2 inhibitor treatment, ChIP for H3K27me3 at CD58 promoter, flow cytometry for CD58 expression, T/NK cell IFN-gamma production co-culture assay Molecular immunology High 31962268
2020 T-cell rosetting in Hodgkin lymphoma is established by CD2-CD58 interaction forming an immunological synapse; CD58 knockout or CD2 blockade reduces rosette formation and T-cell activation; T-cell activation additionally requires TCR-HLA-II interaction, as shown by CIITA knockout. HL cell line coculture rosetting model, CRISPR knockout of CIITA and CD58, CD2 blocking antibodies, proximity ligation assay in primary HL tissue Blood High 32589698
2022 CD58 loss in tumor cells impairs CAR T cell function by inducing formation of suboptimal immunological synapses, reducing CAR T cell expansion, degranulation, cytokine secretion, and cytotoxicity; CD58 was identified as a top resistance gene via genome-wide CRISPR/Cas9 screen. Genome-wide CRISPR/Cas9 screen, CD58 KO validation in vitro and in vivo, immunological synapse imaging, degranulation and cytokine assays Blood advances High 35728062
2022 PAX5 acts as a transcriptional activator of CD58 via a PAX5-driven enhancer at the CD58 locus; the PAX5 P80R mutation disrupts this enhancer, reducing CD58 expression and blinatumomab sensitivity in B-ALL. Genome-wide CRISPR screen for blinatumomab sensitivity, transcription factor CRISPR screen (1639 genes), genome editing of PAX5 P80R, ChIP/ATAC-seq for enhancer identification, patient blast validation Science advances High 36516256
2023 CMTM6 is critical for CD58 protein stability; CMTM6 binding determines the balance between endosomal recycling and lysosomal degradation of CD58; CD58 and PD-L1 compete for CMTM6 binding such that loss of CD58 increases PD-L1 protein stabilization (and vice versa). CRISPR-Cas9 screens, proteomics screens, co-IP of CD58 and PD-L1 with CMTM6, endosomal recycling and lysosomal degradation assays, humanized mouse models, patient melanoma scRNA-seq Cancer cell High 37327789
2024 CD58 inhibits JAK2/STAT1 pathway activity by activating the LYN/CD22/SHP1 axis; loss of CD58 in DLBCL leads to elevated JAK2/STAT1 activity, increased PDL1 and IDO expression, and immune evasion; combination of CD58-CD2 costimulatory signaling with anti-PDL1 or IDO inhibitor sensitizes CD58-deficient DLBCL to CAR T cell therapy. Co-IP, RNA-seq, whole-exome sequencing, scRNA-seq, DLBCL patient samples, CAR T cell co-culture functional assays, pathway inhibitor experiments Cancer research Medium 38635903
2024 HSPA4 upregulation increases ALKBH5 protein stability, which in turn decreases CD58 expression in gastric cancer cells through m6A methylation regulation; this reduces CD8+ T cell cytotoxicity and activates PD1/PDL1 axis. Co-immunoprecipitation, meRIP (m6A RNA immunoprecipitation), CD8+ T cell co-culture cytotoxicity assay, HSPA4 overexpression experiments Journal of experimental & clinical cancer research Medium 38589927
1993 A soluble form of CD58 (sCD58) is present in human serum, urine, and cell line supernatants; purified sCD58 binds to CD2-positive T cells and at high concentrations inhibits rosette formation, suggesting sCD58 can act as an immunosuppressive factor by competing with membrane-bound CD58 for CD2 binding. ELISA for CD58, gel filtration, SDS-PAGE/Western blot, rosette inhibition assay with purified sCD58 European journal of immunology Medium 7693485
2015 CD58/CD2 is the primary costimulatory pathway for CD28-negative CD8+ T cells; CD58 broadly expressed on APCs (including dendritic cells) engages CD2 to costimulate proliferation, cytokine production, and effector function of CD28-CD8+ T cells; blocking CD58 mAb greatly reduces responses to allogeneic DCs and viral antigens. mAb blocking of CD58 in CD28-CD8+ T cell stimulation assays with DCs, allogeneic and viral antigen responses, proliferation and cytokine measurements Journal of immunology High 26041540

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1982 Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proceedings of the National Academy of Sciences of the United States of America 884 6984191
1987 An LFA-3 cDNA encodes a phospholipid-linked membrane protein homologous to its receptor CD2. Nature 742 3313052
1983 The functional significance, distribution, and structure of LFA-1, LFA-2, and LFA-3: cell surface antigens associated with CTL-target interactions. Journal of immunology (Baltimore, Md. : 1950) 694 6345670
1987 The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3. Nature 520 2951597
1992 Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 455 1372018
2011 Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer cell 372 22137796
1990 LFA-3, CD44, and CD45: physiologic triggers of human monocyte TNF and IL-1 release. Science (New York, N.Y.) 318 1697984
2009 Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nature genetics 284 19898481
1984 LFA-1, LFA-2, and LFA-3 antigens are involved in CTL-target conjugation. Journal of immunology (Baltimore, Md. : 1950) 266 6201533
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