{"gene":"CD58","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1987,"finding":"CD2 (LFA-2/T11) directly binds LFA-3 (CD58) on cell surfaces, mediating T cell adhesion to lymphoid cells; purified CD2 inhibits T-cell rosetting with human erythrocytes and is absorbed by sheep erythrocytes expressing LFA-3, establishing CD58 as the natural ligand for CD2.","method":"Ligand binding with purified protein, rosette inhibition assay, absorption experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein binding demonstrated, replicated across multiple labs and confirmed with reciprocal inhibition assays","pmids":["2951597","3102675"],"is_preprint":false},{"year":1983,"finding":"LFA-3 (CD58) is widely distributed on hematopoietic and non-hematopoietic tissues; anti-LFA-3 monoclonal antibodies block CTL-mediated cytolysis by binding to target cells (not effector cells), indicating CD58 functions on target cells in CTL interactions.","method":"Monoclonal antibody generation and 51Cr-release cytotoxicity blocking assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent labs confirmed target-cell-side function of LFA-3 in CTL killing","pmids":["6345670"],"is_preprint":false},{"year":1994,"finding":"Human CD2 binds CD58 with very low affinity (Kd 9–22 µM) and an extremely fast dissociation rate (koff ≥ 4 s⁻¹); CD2 does not detectably bind CD48 or CD59 under the same conditions, establishing CD58 as the primary high-specificity ligand for human CD2.","method":"Surface plasmon resonance (BIAcore) with soluble recombinant ectodomains","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous biophysical measurement with recombinant proteins, defining quantitative kinetic parameters","pmids":["7520278"],"is_preprint":false},{"year":1999,"finding":"Crystal structure of the CD2-binding domain of CD58 at 1.8-Å resolution reveals an Ig superfamily V-set topology shared with CD2; the ligand-binding surface of CD58 is the highly acidic AGFCC'C\" beta-sheet face; mutations that disrupt CD2 binding map to this surface, and the interface lacks strong shape complementarity, suggesting electrostatic complementarity drives specificity.","method":"X-ray crystallography at 1.8 Å with functional mutagenesis validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis in a single study","pmids":["10200255"],"is_preprint":false},{"year":1993,"finding":"The CD58-binding site on CD2 maps to the major AGFCC'C\" beta-sheet face of domain 1; substitution of residues K34, E36 (strand C), R48, K49 (strand C'), and K91, N92 (FG loop) abrogates rosetting with human and sheep erythrocytes, demonstrating that these charged residues are critical for CD2–CD58 interaction.","method":"Site-directed mutagenesis of CD2 combined with rosetting assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with functional readout, consistent with structural data","pmids":["7688025"],"is_preprint":false},{"year":1994,"finding":"The CD58 binding surface on CD2 involves residues on the C, C', and CC' loop strands; mutating charged residues E25, K29, K30 (C strand), E37 (C' strand), K32, D33, K34 (CC' loop), and K87 (G strand) of CD58 reduces CD2 binding, establishing that CD2–CD58 interaction involves the major beta-sheet surface of each adhesion domain in a 'handshake' orientation.","method":"Site-directed mutagenesis of CD58 combined with cell adhesion and rosetting assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of CD58, confirmed with multiple binding assays","pmids":["7525842"],"is_preprint":false},{"year":1999,"finding":"NMR solution structure of a glycan-free CD58 adhesion domain confirms binding to CD2 involves the GFCC'C\" faces of both molecules; chemical shift perturbations in NMR titration localize the binding site to C, C', and C\" strands and loops of CD58.","method":"NMR spectroscopy with titration experiments using recombinant CD58 adhesion domain","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional binding validation in same study","pmids":["10357807"],"is_preprint":false},{"year":2001,"finding":"The functional hot spot of the CD2–CD58 interface is defined by CD2 Tyr86 and CD58 Lys34; alanine scanning of salt-bridge residues shows D31A, D32A, K34A, K43A, R48A reduce affinity 47–127-fold, while Y86A reduces affinity ~1000-fold; crystal structure analysis shows CD2 Y86 makes hydrophobic contact with the aliphatic chain of CD58 K34.","method":"Isothermal titration calorimetry with alanine-scanning mutagenesis; crystal structure analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative calorimetry and structural analysis in single study with systematic mutagenesis","pmids":["11575926"],"is_preprint":false},{"year":2001,"finding":"CD58 engagement of CD2 on T cells activates AP-1, NF-AT, NF-κB, and NF-IL-2 transcriptional pathways and promotes lipid raft aggregation on T cells, amplifying TCR signaling; anti-CD2 antibodies block all these effects and EC-induced raft aggregation.","method":"Luciferase reporter assays for transcription factors, lipid raft aggregation assay with CD2 blocking antibodies in CD58-expressing endothelial cell co-cultures","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in single lab, mechanistic pathway analysis with blocking controls","pmids":["11591762"],"is_preprint":false},{"year":1988,"finding":"LFA-3 activates T cells via CD2 under appropriate conditions, but this activation requires both cell surface expression of CD3/TCR complex and a functional antigen receptor pathway; a CD3-negative CD2+ Jurkat mutant fails to respond to LFA-3 plus anti-CD2, and TCR-β chain transfection restores responsiveness.","method":"Genetic reconstitution in Jurkat mutants; calcium flux and phosphatidylinositol hydrolysis assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by reconstitution with multiple biochemical readouts, replicated across multiple mutant lines","pmids":["2459194"],"is_preprint":false},{"year":1991,"finding":"GPI-anchored LFA-3 (CD58) diffuses laterally in membranes with a coefficient approaching phospholipids, whereas transmembrane LFA-3 is immobile; GPI-anchored LFA-3 supports faster and more efficient adhesion strengthening with CD2+ T cells at low site densities due to receptor accumulation in the contact zone.","method":"Reconstituted planar lipid bilayers with two LFA-3 isoforms; static and laminar flow adhesion assays; fluorescence recovery measurements","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted system with controlled receptor density, multiple assay formats, quantitative kinetic measurements","pmids":["1717480"],"is_preprint":false},{"year":1998,"finding":"Both the GPI-anchored and transmembrane forms of CD58 associate with protein kinase(s); crosslinking either isoform with immobilized anti-CD58 antibodies induces extensive tyrosine phosphorylation and TNF-alpha secretion in B cells, establishing CD58's role in signal transduction independent of anchor type.","method":"Immunoprecipitation kinase assay; comparison of JY variant cells expressing only one isoform; anti-CD58 crosslinking with tyrosine phosphorylation readout","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-immunoprecipitation with kinase assay, isoform-specific variant cell lines","pmids":["9574540"],"is_preprint":false},{"year":1994,"finding":"Ligation of B cell CD58 by CD2 or by anti-CD58 monoclonal antibody provides an IL-4-dependent signal that drives IgE class switch recombination (inducing productive ε transcripts and IgE protein production) distinct from the CD40 pathway; direct CD2 involvement was confirmed by co-culture with CD2-transfected T hybridoma cells.","method":"Purified B cells co-stimulated with IL-4 and anti-CD58 mAb; RT-PCR for ε transcripts; ELISA for IgE; CD40-Fc fusion protein competition; CD2-transfected hybridoma co-culture","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including genetic (CD2 transfectants), blocking antibodies, and molecular (transcript) readouts","pmids":["7515920"],"is_preprint":false},{"year":1996,"finding":"CD2–CD58 interaction between T cells and monocytes specifically regulates T cell responsiveness to IL-12; CHO cells expressing CD58 at monocyte-equivalent levels restore IL-12 responsiveness to APC-depleted T cells, whereas CD48-expressing CHO cells (low avidity CD2 ligand) do not, demonstrating that high-avidity CD58–CD2 ligation is required for IL-12 co-signaling.","method":"APC-depletion experiments; CD58-transfected CHO cell reconstitution; proliferation assays; anti-CD2/CD58 blocking antibodies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution with CHO transfectants, specificity shown by CD48 negative control, multiple functional readouts","pmids":["8757306"],"is_preprint":false},{"year":1993,"finding":"TCR stimulation rapidly upregulates CD2 avidity for CD58; this regulation requires both protein tyrosine kinase activity and protein kinase C activity, and requires the carboxyl-terminal asparagine of the CD2 cytoplasmic domain; cAMP elevation also upregulates CD2 avidity through the same structural element.","method":"CD2 avidity assay (cell binding to purified CD58 and SRBC rosetting); kinase inhibitors; CD2 cytoplasmic domain single amino acid substitution mutants in Jurkat hybridomas","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis of CD2 cytoplasmic domain, multiple pharmacological inhibitors, functional binding readout","pmids":["7681075"],"is_preprint":false},{"year":2006,"finding":"T cell activation increases CD2 surface expression 1.5-fold and the 2D affinity of CD2 for CD58 2.5-fold; combined T cell activation and CD2 ligation to CD58 decreases the laterally mobile fraction of CD2, consistent with cytoskeletal immobilization at the contact site to strengthen T cell–APC adhesion.","method":"Fluorescence recovery after photobleaching (FRAP); quantitative surface receptor measurements; 2D affinity measurements on supported lipid bilayers","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative biophysical measurements, single lab, multiple orthogonal methods","pmids":["17168569"],"is_preprint":false},{"year":2003,"finding":"Steered molecular dynamics simulations show that at slow loading rates CD2 and CD58 separate before unfolding; salt bridges primarily determine tensile strength of the CD2–CD58 bond, and the order of salt bridge rupture correlates with their position relative to the force vector; simulation results correlate with cell aggregation and equilibrium binding data from site-directed mutagenesis.","method":"Steered molecular dynamics simulations; correlation with published mutagenesis data","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — computational simulation with validation against experimental mutagenesis data; single study","pmids":["12668431"],"is_preprint":false},{"year":2006,"finding":"Quantitative surface force apparatus measurements confirm that single charge mutations at CD2 D31, K41, K51, K91 alter both solution-phase binding kinetics (SPR) and cell adhesion strength for the CD2–CD58 interaction, validating the role of specific salt bridges in adhesion.","method":"Surface plasmon resonance; surface force apparatus adhesion measurements with CD2 charge mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — two orthogonal quantitative methods, single lab","pmids":["17172599"],"is_preprint":false},{"year":1989,"finding":"Anti-LFA-3 monoclonal antibody crosslinks LFA-3 and induces lateral immobilization of class I and class II MHC proteins in the plasma membrane of B cells, suggesting that CD2 binding to LFA-3 on target cells may immobilize and concentrate MHC molecules at the T cell–target cell interface.","method":"Fluorescence photobleaching recovery (FPR) on JY B cells; bivalent vs. monovalent fluorescent antibody comparison","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative membrane mobility assay with multiple molecular targets and controls, single lab","pmids":["2471647"],"is_preprint":false},{"year":1998,"finding":"NK cell lysis of CMV-infected fibroblasts correlates with upregulation of LFA-3 (CD58) on infected cells, not with MHC class I downregulation; viral strains that upregulate LFA-3 render cells susceptible to NK killing, while strains that downregulate LFA-3 make cells resistant; a minimum of 29,000–71,000 LFA-3 molecules per target are required for NK susceptibility.","method":"NK cytotoxicity assay with multiple CMV strains; flow cytometry for LFA-3 and MHC I; quantitative threshold analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple viral strains used as natural genetic variation, quantitative threshold established, consistent across different cell types","pmids":["9725232"],"is_preprint":false},{"year":2003,"finding":"Coexpression of CD58 (or CD48) with ICAM-1 on target cells enhances adhesion of resting NK cells beyond that mediated by ICAM-1 alone, in the absence of cytokine priming; receptors for LFA-3 on resting NK cells strengthen LFA-1–mediated adhesion.","method":"Drosophila cells expressing defined combinations of human ligands; NK cell adhesion assays with kinase inhibitors","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstituted system with Drosophila cells expressing defined ligands, single lab","pmids":["12496412"],"is_preprint":false},{"year":2023,"finding":"CMTM6 is required for CD58 protein stability; loss of CD58 leads to increased PD-L1 protein stabilization because CD58 and PD-L1 compete for CMTM6 binding, which determines their rate of endosomal recycling versus lysosomal degradation; intact cancer cell CD58 expression and ligation of CD2 is required for anti-tumor immunity and predicts checkpoint blockade response.","method":"CRISPR-Cas9 screens; proteomics; patient-derived co-cultures; humanized mouse models; single-cell RNA-seq of patient biopsies; co-immunoprecipitation for CMTM6 interactions","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, proteomics, co-IP, in vivo models, patient samples) in one study","pmids":["37327789"],"is_preprint":false},{"year":2020,"finding":"EZH2 epigenetically silences CD58 expression in B-cell lymphoma cells through H3K27 trimethylation at the CD58 promoter; EZH2 inhibitors (EPZ6438, GSK126) restore CD58 expression by demethylating H3K27me3 at the CD58 locus and enhance T/NK cell IFN-γ production against lymphoma cells.","method":"Epigenetic inhibitor library screen; ChIP for H3K27me3 at CD58 promoter; flow cytometry; IFN-γ functional assay","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates H3K27me3 at promoter, functional rescue with pharmacological inhibitors, single lab","pmids":["31962268"],"is_preprint":false},{"year":2022,"finding":"PAX5 is the key transcriptional activator of CD58 in B-ALL; PAX5 P80R mutation disrupts a PAX5-driven enhancer at the CD58 locus, reducing CD58 expression; loss of CD58 confers resistance to blinatumomab by abolishing blinatumomab-induced T cell activation; identified by genome-wide CRISPR screen followed by transcription factor screen of 1639 genes.","method":"Genome-wide CRISPR screen; transcription factor CRISPR screen; genome editing to introduce/correct PAX5 P80R; ChIP/ATAC-seq for enhancer; co-culture cytotoxicity assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen validated by genome editing, epigenomic mapping, and functional assays in single study","pmids":["36516256"],"is_preprint":false},{"year":2024,"finding":"CD58 inhibits JAK2/STAT1 pathway activity by activating the LYN/CD22/SHP1 axis; loss of CD58 in DLBCL leads to elevated PDL1 and IDO expression through this pathway, contributing to immune evasion; direct CD58–CD2 costimulation combined with anti-PDL1 or IDO inhibitor sensitizes CD58-deficient DLBCL to CAR-T therapy.","method":"Targeted NGS, RNA-seq, WES, scRNA-seq; co-IP for pathway components; pharmacological inhibitor combinations; CAR-T cytotoxicity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for LYN/CD22/SHP1 axis, multiple orthogonal analyses, single lab","pmids":["38635903"],"is_preprint":false},{"year":2024,"finding":"HSPA4 upregulation increases ALKBH5 protein stability; ALKBH5 (m6A demethylase) decreases CD58 mRNA in gastric cancer cells through m6A methylation regulation, reducing CD8+ T cell cytotoxicity and activating PD1/PDL1 axis.","method":"Co-immunoprecipitation; meRIP (m6A RNA immunoprecipitation); co-culture cytotoxicity assay; HSPA4 overexpression/knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and meRIP establish mechanism, functional cytotoxicity readout, single lab","pmids":["38589927"],"is_preprint":false},{"year":1988,"finding":"CD2 expression on a murine T cell hybridoma greatly enhances T cell responsiveness to antigen in an LFA-3-dependent manner; a CD2 mutant lacking the mAb 9.6 epitope loses both enhanced antigen responsiveness and LFA-3-driven activation but retains activation by anti-CD2 antibody pairs, indicating the CD2–LFA-3 interaction requires an intact CD2 extracellular epitope.","method":"cDNA expression of wild-type and mutant CD2 in murine T cell hybridoma; IL-2 production assays; anti-CD2 and anti-LFA-3 blocking antibodies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution of human CD2 in murine cells with epitope-loss mutant, functional IL-2 production readout","pmids":["2448792"],"is_preprint":false},{"year":2022,"finding":"Genome-wide CRISPR/Cas9 screen identifies CD58 loss as a mechanism of tumor resistance to CAR T cell therapy; CD58-deficient tumor cells form suboptimal immunological synapses with CAR T cells, impairing CAR T cell expansion, degranulation, cytokine secretion, and cytotoxicity in vitro and in vivo.","method":"Genome-wide CRISPR/Cas9 screen; CD58 knockout validation; in vitro CAR T functional assays; in vivo xenograft model; immunological synapse analysis","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screen validated by targeted KO, multiple functional readouts, in vivo confirmation","pmids":["35728062"],"is_preprint":false},{"year":2015,"finding":"CD58/CD2 axis is the primary costimulatory pathway in CD28-negative CD8+ T cells; CD58 on APCs (including dendritic cells) engages CD2 on CD28⁻CD8⁺ T cells to costimulate proliferation, cytokine production, and effector function; CD2 engagement amplifies TCR signals in this subset.","method":"Blocking anti-CD58 mAb in allogeneic DC assays; viral antigen recall responses; T cell proliferation and cytokine assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking experiments with multiple readouts, single lab","pmids":["26041540"],"is_preprint":false},{"year":2009,"finding":"The protective rs2300747(G) allele of CD58 is associated with dose-dependent increases in CD58 mRNA expression in lymphoblastic cell lines and PBMCs; increased CD58 expression upregulates FoxP3 expression through engagement of CD2, enhancing function of CD4+CD25high regulatory T cells.","method":"Fine mapping and resequencing; dose-dependent mRNA expression analysis; functional CD58–CD2 engagement assay measuring FoxP3 induction","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic variant linked to expression and functional outcome via CD2 engagement, single lab","pmids":["19237575"],"is_preprint":false},{"year":1999,"finding":"CD58 is expressed constitutively on the basolateral surface of polarized intestinal epithelial cells (but not CD80 or CD86); this basolateral CD58 acts as the costimulatory molecule mediating HLA class II antigen presentation to CD4+ T cells, as anti-CD58 antibodies block IEC-stimulated T cell proliferation while anti-CD80/CD86 do not.","method":"Flow cytometry; confocal microscopy; vectorial biotinylation to determine polarized localization; antibody blocking of T cell proliferation","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by vectorial biotinylation linked to functional consequence, single lab","pmids":["10220497"],"is_preprint":false},{"year":1993,"finding":"CMV infection directly upregulates LFA-3 and ICAM-1 cell-surface expression on fibroblasts; this is a direct viral effect (not cytokine-mediated) requiring infectious virus; LFA-3 accumulates in perinuclear granules in infected cells vs. diffuse cytoplasmic distribution in uninfected cells.","method":"Flow cytometry; neutralizing antibody experiments against candidate cytokines; UV-inactivated virus controls; confocal scanning laser microscopy; immunofluorescence","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple controls (UV-inactivated virus, cytokine neutralization), imaging-confirmed localization change, single lab","pmids":["7682988"],"is_preprint":false},{"year":2016,"finding":"CD2–CD58 binding is required for activation and effector functions of adaptive (NKG2C+CD57+) NK cells in response to HCMV-infected cells; antibody blockade of CD2 or CD58 largely blocks upregulation of activation markers (CD69, CD25, HLA-DR) and production of IFN-γ and TNF-α specifically in adaptive NK cells.","method":"Co-culture of human PBMCs with HCMV-infected fibroblasts; CD2/CD58 blocking antibodies; flow cytometry for activation markers and intracellular cytokines","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with multiple readouts, subset-specific analysis, single lab","pmids":["27469079"],"is_preprint":false},{"year":2020,"finding":"CD58 expression on Hodgkin lymphoma Reed-Sternberg cells determines extent of T cell rosette formation and T cell activation; CD58 knockout or CD2 blockade reduces both rosetting and T cell activation; proximity ligation assays in primary HL tissue confirm CD2–CD58 interactions at the immunological synapse.","method":"CD58 knockout by CRISPR (CIITA KO for HLA-II comparison); rosetting co-culture model; proximity ligation assay on primary tissue; flow cytometry for T cell activation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with functional readout, validated in primary patient tissue by proximity ligation assay","pmids":["32589698"],"is_preprint":false},{"year":2014,"finding":"CD58 promotes self-renewal of colorectal tumor-initiating cells by upregulating the Wnt/β-catenin pathway through degradation of Dickkopf 3 (DKK3); CD58 knockdown impairs sphere formation and tumor growth; CD58–DKK3 interaction identified by co-immunoprecipitation and western blotting.","method":"cDNA GeneChip; flow cytometry; sphere formation assay; xenograft in vivo; co-immunoprecipitation and western blot for DKK3 degradation; lentiviral CD58 knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional pathway validation in vitro and in vivo, single lab","pmids":["24727892"],"is_preprint":false},{"year":1998,"finding":"MHC class II ligation induces homotypic T cell adhesion that is almost completely inhibited by anti-CD58 antibody and partly by anti-CD2 antibody, establishing that CD58–CD2 interaction is required for class-II-induced T cell aggregation; demonstrated in β2-integrin-deficient T cells confirming β2-integrin independence.","method":"Cell aggregation assay with blocking monoclonal antibodies in β2-integrin-negative (LAD patient) T cell lines","journal":"Experimental and clinical immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic variant cell lines (LAD patient), multiple antibody blockades, single lab","pmids":["9691200"],"is_preprint":false},{"year":1993,"finding":"Soluble CD58 (sCD58) is present as a natural protein in human serum, urine, and cell culture supernatants; it forms noncovalent homotrimers (~118–166 kDa by gel filtration) and at high concentrations binds to CD2+ T cells and inhibits rosette formation, suggesting sCD58 can suppress CD2–CD58-mediated adhesion in vivo.","method":"ELISA; SDS-PAGE and Western blotting; gel filtration; T cell rosette inhibition assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with functional inhibition assay, single lab","pmids":["7693485"],"is_preprint":false}],"current_model":"CD58 (LFA-3) is a broadly expressed Ig-superfamily cell adhesion and costimulatory molecule that functions as the primary high-specificity ligand for CD2 on T and NK cells, binding through complementary charged beta-sheet surfaces (with CD2 Tyr86–CD58 Lys34 as the functional hot spot) with very low affinity and fast kinetics; it promotes T/NK cell adhesion, immunological synapse formation, and costimulatory signaling by amplifying TCR-proximal signals via lipid raft aggregation, regulates T cell IL-12 responsiveness, drives IgE class switching, and is epigenetically controlled by EZH2 (H3K27me3) and transcriptionally activated by PAX5; CD58 protein stability is maintained by CMTM6, which also controls PD-L1 stability through competitive recycling, and CD58 loss in cancer cells promotes immune evasion by forming suboptimal immunological synapses, stabilizing PD-L1, and activating IDO through the LYN/CD22/SHP1 axis."},"narrative":{"mechanistic_narrative":"CD58 (LFA-3) is a broadly distributed immunoglobulin-superfamily cell-surface adhesion and costimulatory molecule that serves as the principal high-specificity ligand for CD2 on T and NK cells, governing the formation and quality of the immunological synapse [PMID:2951597, PMID:3102675, PMID:7520278]. The CD58 adhesion domain is a V-set Ig fold whose highly acidic AGFCC'C\" beta-sheet face docks against the equivalent surface of CD2 in a charge-complementary \"handshake\"; the interaction is of very low affinity (Kd ~9-22 µM) with extremely fast dissociation kinetics, with electrostatic salt bridges driving specificity and the CD2 Tyr86-CD58 Lys34 contact acting as the dominant energetic hot spot [PMID:7520278, PMID:10200255, PMID:7525842, PMID:10357807, PMID:11575926]. By engaging CD2, CD58 on antigen-presenting and target cells amplifies TCR-proximal signaling through lipid-raft aggregation and activation of AP-1, NF-AT, NF-κB and NF-IL-2 pathways, but this costimulation requires an intact CD3/TCR complex [PMID:11591762, PMID:2459194]. CD58 functions on the target/APC side of cytolytic and adhesive interactions: it supports CTL killing, MHC-class-II-driven T cell costimulation and adhesion, IL-12 responsiveness, IgE class switching in B cells, and NK cell activation against virally infected targets, and it is the primary costimulatory pathway for CD28-negative CD8+ T cells [PMID:6345670, PMID:11591762, PMID:7515920, PMID:8757306, PMID:9725232, PMID:26041540, PMID:9691200]. CD58 surface levels are set at multiple regulatory layers: PAX5 transcriptionally activates a CD58 enhancer, EZH2-mediated H3K27me3 silences the locus, ALKBH5-dependent m6A regulation destabilizes its mRNA, and CMTM6 stabilizes the CD58 protein by controlling its endosomal recycling versus lysosomal degradation in competition with PD-L1 [PMID:37327789, PMID:31962268, PMID:36516256, PMID:38589927]. Loss of CD58 is a recurrent mechanism of tumor immune evasion: it produces suboptimal immunological synapses that impair CAR-T and endogenous T/NK effector function, stabilizes PD-L1, and activates IDO via the LYN/CD22/SHP1 axis, and CD58 status predicts response to immune checkpoint and immunotherapy [PMID:37327789, PMID:38635903, PMID:35728062, PMID:32589698].","teleology":[{"year":1983,"claim":"Established that CD58 acts on the target-cell side of cytolytic interactions, reframing it from a generic surface antigen to a functional partner in immune effector recognition.","evidence":"Anti-LFA-3 monoclonal antibody blocking of CTL-mediated cytolysis in 51Cr-release assays, mapping function to target cells","pmids":["6345670"],"confidence":"High","gaps":["Molecular binding partner of CD58 not yet identified","Mechanism of how CD58 promotes killing not defined"]},{"year":1987,"claim":"Identified CD2 as the direct binding partner of CD58, defining the receptor-ligand axis underlying T cell adhesion to lymphoid and target cells.","evidence":"Purified-protein ligand binding, rosette inhibition, and erythrocyte absorption experiments","pmids":["2951597","3102675"],"confidence":"High","gaps":["Binding affinity and kinetics not quantified","Structural basis of recognition unknown"]},{"year":1988,"claim":"Showed that CD58-CD2 engagement requires the antigen-receptor machinery to deliver activation signals, linking the adhesion axis to TCR-dependent T cell activation rather than independent signaling.","evidence":"Genetic reconstitution of CD3-negative Jurkat mutants with TCR-beta and CD2 epitope-loss mutants, with calcium flux and PI hydrolysis readouts","pmids":["2459194","2448792"],"confidence":"High","gaps":["Downstream signaling intermediates not mapped","Quantitative contribution of CD58 versus TCR signal not separated"]},{"year":1994,"claim":"Quantified the CD2-CD58 interaction as very-low-affinity and fast-dissociating and established CD58 as the high-specificity ligand over CD48/CD59, explaining the kinetics that permit rapid, transient adhesion.","evidence":"Surface plasmon resonance with soluble recombinant ectodomains","pmids":["7520278"],"confidence":"High","gaps":["Structural interface not resolved","How fast kinetics support stable synapse adhesion unresolved"]},{"year":1994,"claim":"Defined the molecular interface as the charged AGFCC'C\" beta-sheet faces of both partners, providing a structural rationale for electrostatically driven specificity.","evidence":"Reciprocal site-directed mutagenesis of CD2 and CD58 charged residues with rosetting and adhesion assays","pmids":["7688025","7525842"],"confidence":"High","gaps":["Energetic hierarchy of individual contacts not yet established","No high-resolution structure of the complex interface"]},{"year":1999,"claim":"Resolved the CD58 adhesion domain structure, confirming a V-set Ig fold sharing topology with CD2 and an acidic ligand-binding face with poor shape complementarity, supporting an electrostatically driven recognition model.","evidence":"1.8-Å X-ray crystallography and NMR solution structure with mutagenesis and titration validation","pmids":["10200255","10357807"],"confidence":"High","gaps":["Full co-complex thermodynamics not yet measured","Role of glycosylation in vivo not addressed"]},{"year":2001,"claim":"Pinpointed CD2 Tyr86-CD58 Lys34 as the dominant energetic hot spot, refining the binding model from uniformly distributed electrostatics to a defined hydrophobic anchor amid salt bridges.","evidence":"Isothermal titration calorimetry with alanine-scanning mutagenesis and crystal structure analysis","pmids":["11575926"],"confidence":"High","gaps":["Hot spot contribution to physiological adhesion strength not directly tested at the cell level here"]},{"year":2001,"claim":"Linked CD58-CD2 engagement to defined transcriptional programs and membrane reorganization, establishing CD58 as a costimulus that amplifies TCR signaling via lipid raft aggregation.","evidence":"Luciferase reporters for AP-1/NF-AT/NF-κB/NF-IL-2 and lipid raft aggregation assays with CD2 blocking antibodies in endothelial co-cultures","pmids":["11591762"],"confidence":"Medium","gaps":["Single-lab functional pathway analysis","Direct molecular link between CD2 engagement and raft coalescence not defined"]},{"year":2006,"claim":"Connected molecular binding properties to physical adhesion mechanics, showing salt bridges set the tensile strength of the bond and that activation tunes CD2 2D affinity and mobility to strengthen contact.","evidence":"Steered molecular dynamics, surface force apparatus, SPR, and FRAP on supported bilayers with CD2 charge mutants","pmids":["12668431","17172599","17168569"],"confidence":"Medium","gaps":["Computational and biophysical models from single labs","In vivo relevance of force-dependent rupture not tested"]},{"year":1994,"claim":"Demonstrated that CD58 signals beyond adhesion, driving IL-4-dependent IgE class switching and IL-12 responsiveness, broadening its role into B cell and T cell effector programming.","evidence":"Anti-CD58/CD2 ligation of B cells with epsilon transcript and IgE readouts; CD58-transfected CHO reconstitution of IL-12 responsiveness with CD48 negative control","pmids":["7515920","8757306"],"confidence":"High","gaps":["Signaling intermediates downstream of CD58 ligation not mapped","Whether B cell CD58 signals cell-autonomously versus via CD2 partner cell unresolved"]},{"year":1998,"claim":"Established CD58 as a determinant of NK-mediated immunity against viral infection, with a quantitative surface-density threshold governing target susceptibility.","evidence":"NK cytotoxicity assays across CMV strains with flow cytometry quantification of LFA-3 density","pmids":["9725232","7682988"],"confidence":"High","gaps":["Mechanism by which CMV upregulates CD58 not defined","Receptor on NK cells (CD2) contribution not formally isolated in this study"]},{"year":2020,"claim":"Identified transcriptional and epigenetic control of CD58 expression, showing PAX5 activates and EZH2-mediated H3K27me3 silences the locus, defining mechanisms that set CD58 surface abundance.","evidence":"Epigenetic inhibitor screen with ChIP for H3K27me3 and IFN-γ rescue; genome-wide and transcription-factor CRISPR screens with PAX5 P80R editing and ATAC/ChIP enhancer mapping","pmids":["31962268","36516256"],"confidence":"High","gaps":["Interplay between PAX5 and EZH2 control not integrated","Tissue specificity of these regulatory mechanisms not defined"]},{"year":2023,"claim":"Revealed post-translational control of CD58 by CMTM6, coupling CD58 protein stability to PD-L1 stability through competitive endosomal recycling and providing a mechanistic link between CD58 loss and checkpoint resistance.","evidence":"CRISPR screens, proteomics, co-IP, patient-derived co-cultures, and humanized mouse models","pmids":["37327789"],"confidence":"High","gaps":["Structural basis of CMTM6 competition between CD58 and PD-L1 not resolved","Whether other CMTM family members participate not addressed"]},{"year":2024,"claim":"Extended CD58 loss to active immune evasion signaling, showing it represses JAK2/STAT1 via the LYN/CD22/SHP1 axis to elevate PD-L1 and IDO, and that m6A regulation destabilizes CD58 mRNA in cancer.","evidence":"Co-IP for LYN/CD22/SHP1 and HSPA4/ALKBH5, meRIP, RNA-seq/WES/scRNA-seq, and CAR-T/cytotoxicity combination assays","pmids":["38635903","38589927"],"confidence":"Medium","gaps":["Single-lab mechanistic chains awaiting orthogonal confirmation","How CD58 surface engagement transduces into intracellular JAK2/STAT1 suppression not fully defined"]},{"year":2022,"claim":"Established CD58 loss as a clinically relevant mechanism of immunotherapy resistance, with deficient cells forming suboptimal synapses that cripple CAR-T and endogenous effector function.","evidence":"Genome-wide CRISPR screens with knockout validation, in vitro/in vivo CAR-T functional assays, rosetting and proximity ligation assays in primary lymphoma tissue","pmids":["35728062","32589698"],"confidence":"High","gaps":["Quantitative synapse defect not mechanistically linked to specific signaling deficits","Strategies to restore CD58 in vivo not established"]},{"year":null,"claim":"How the multiple layers of CD58 regulation (PAX5/EZH2 transcription, ALKBH5 m6A, CMTM6 protein stability, soluble CD58 shedding) are integrated to set functional surface density across tissues and tumor contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking transcriptional, epigenetic, m6A, and protein-stability control","Physiological role of soluble homotrimeric CD58 in modulating adhesion in vivo not established","Intracellular signaling consequences of CD58 ligation in non-canonical pathways (Wnt/DKK3, JAK2/STAT1) not mechanistically connected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8,28]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,13,28]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,24,27]}],"complexes":[],"partners":["CD2","CMTM6","DKK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19256","full_name":"Lymphocyte function-associated antigen 3","aliases":["Surface glycoprotein LFA-3"],"length_aa":250,"mass_kda":28.1,"function":"Ligand of the T-lymphocyte CD2 glycoprotein. This interaction is important in mediating thymocyte interactions with thymic epithelial cells, antigen-independent and -dependent interactions of T-lymphocytes with target cells and antigen-presenting cells and the T-lymphocyte rosetting with erythrocytes. In addition, the LFA-3/CD2 interaction may prime response by both the CD2+ and LFA-3+ cells","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P19256/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD58","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD58","total_profiled":1310},"omim":[{"mim_id":"614711","title":"FAMILY WITH SEQUENCE SIMILARITY 72, MEMBER B; FAM72B","url":"https://www.omim.org/entry/614711"},{"mim_id":"606620","title":"SLAM FAMILY, MEMBER 8; SLAMF8","url":"https://www.omim.org/entry/606620"},{"mim_id":"604516","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 2; IGSF2","url":"https://www.omim.org/entry/604516"},{"mim_id":"604470","title":"CD2 ANTIGEN-BINDING PROTEIN 2; CD2BP2","url":"https://www.omim.org/entry/604470"},{"mim_id":"602069","title":"NEUROPILIN 1; NRP1","url":"https://www.omim.org/entry/602069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD58"},"hgnc":{"alias_symbol":[],"prev_symbol":["LFA3"]},"alphafold":{"accession":"P19256","domains":[{"cath_id":"2.60.40.10","chopping":"28-122","consensus_level":"high","plddt":92.9606,"start":28,"end":122},{"cath_id":"2.60.40,2.60.40","chopping":"129-206","consensus_level":"high","plddt":92.3354,"start":129,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19256","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19256-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19256-F1-predicted_aligned_error_v6.png","plddt_mean":82.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD58","jax_strain_url":"https://www.jax.org/strain/search?query=CD58"},"sequence":{"accession":"P19256","fasta_url":"https://rest.uniprot.org/uniprotkb/P19256.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19256/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19256"}},"corpus_meta":[{"pmid":"2894392","id":"PMC_2894392","title":"Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production.","date":"1988","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2894392","citation_count":1021,"is_preprint":false},{"pmid":"6345670","id":"PMC_6345670","title":"The functional significance, distribution, and structure of LFA-1, LFA-2, and LFA-3: cell surface antigens associated with CTL-target interactions.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6345670","citation_count":695,"is_preprint":false},{"pmid":"2951597","id":"PMC_2951597","title":"The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3.","date":"1987","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2951597","citation_count":520,"is_preprint":false},{"pmid":"22137796","id":"PMC_22137796","title":"Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22137796","citation_count":374,"is_preprint":false},{"pmid":"2898508","id":"PMC_2898508","title":"Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein-Barr virus-positive Burkitt's lymphoma underlies tumor cell escape from virus-specific T cell surveillance.","date":"1988","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2898508","citation_count":324,"is_preprint":false},{"pmid":"8434643","id":"PMC_8434643","title":"Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8434643","citation_count":194,"is_preprint":false},{"pmid":"7520278","id":"PMC_7520278","title":"Human cell-adhesion molecule CD2 binds CD58 (LFA-3) with a very low affinity and an extremely fast dissociation rate but does not bind CD48 or CD59.","date":"1994","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7520278","citation_count":192,"is_preprint":false},{"pmid":"1377404","id":"PMC_1377404","title":"Overlapping but nonidentical binding sites on CD2 for CD58 and a second ligand CD59.","date":"1992","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1377404","citation_count":179,"is_preprint":false},{"pmid":"1717480","id":"PMC_1717480","title":"Influence of receptor lateral mobility on adhesion strengthening between membranes containing LFA-3 and CD2.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1717480","citation_count":174,"is_preprint":false},{"pmid":"19237575","id":"PMC_19237575","title":"The role of the CD58 locus in multiple sclerosis.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19237575","citation_count":149,"is_preprint":false},{"pmid":"3102675","id":"PMC_3102675","title":"Rosetting of activated human T lymphocytes with autologous erythrocytes. Definition of the receptor and ligand molecules as CD2 and lymphocyte function-associated antigen 3 (LFA-3).","date":"1987","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/3102675","citation_count":148,"is_preprint":false},{"pmid":"2459194","id":"PMC_2459194","title":"The CD2 ligand LFA-3 activates T cells but depends on the expression and function of the antigen receptor.","date":"1988","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2459194","citation_count":147,"is_preprint":false},{"pmid":"8834450","id":"PMC_8834450","title":"T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles.","date":"1995","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8834450","citation_count":129,"is_preprint":false},{"pmid":"7686816","id":"PMC_7686816","title":"Differential expression of cell adhesion molecules CD54/CD11a and CD58/CD2 by human melanoma cells and functional role in their interaction with cytotoxic cells.","date":"1993","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7686816","citation_count":122,"is_preprint":false},{"pmid":"2448792","id":"PMC_2448792","title":"Expression of the T-cell surface molecule CD2 and an epitope-loss CD2 mutant to define the role of lymphocyte function-associated antigen 3 (LFA-3) in T-cell activation.","date":"1988","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2448792","citation_count":112,"is_preprint":false},{"pmid":"1376489","id":"PMC_1376489","title":"Expression and regulation of adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) in human intestinal epithelial cell lines.","date":"1992","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1376489","citation_count":110,"is_preprint":false},{"pmid":"18650830","id":"PMC_18650830","title":"Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.","date":"2008","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18650830","citation_count":106,"is_preprint":false},{"pmid":"1693656","id":"PMC_1693656","title":"Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3.","date":"1990","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1693656","citation_count":103,"is_preprint":false},{"pmid":"7682988","id":"PMC_7682988","title":"Up-regulation of LFA-3 and ICAM-1 on the surface of fibroblasts infected with cytomegalovirus.","date":"1993","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7682988","citation_count":89,"is_preprint":false},{"pmid":"26041540","id":"PMC_26041540","title":"CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28-CD8+ T Cells.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26041540","citation_count":85,"is_preprint":false},{"pmid":"1370512","id":"PMC_1370512","title":"CD58 and CD59 molecules exhibit potentializing effects in T cell adhesion and activation.","date":"1992","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1370512","citation_count":83,"is_preprint":false},{"pmid":"1382543","id":"PMC_1382543","title":"Expression of adhesion molecules LFA-3 and N-CAM on normal and malignant human plasma cells.","date":"1992","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/1382543","citation_count":75,"is_preprint":false},{"pmid":"12496412","id":"PMC_12496412","title":"Coexpression of CD58 or CD48 with intercellular adhesion molecule 1 on target cells enhances adhesion of resting NK cells.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12496412","citation_count":72,"is_preprint":false},{"pmid":"37327789","id":"PMC_37327789","title":"The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.","date":"2023","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/37327789","citation_count":71,"is_preprint":false},{"pmid":"8757306","id":"PMC_8757306","title":"Molecular interaction between CD58 and CD2 counter-receptors mediates the ability of monocytes to augment T cell activation by IL-12.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8757306","citation_count":71,"is_preprint":false},{"pmid":"8900310","id":"PMC_8900310","title":"Cytomegalovirus induced up-regulation of LFA-3 (CD58) and ICAM-1 (CD54) is a direct viral effect that is not prevented by ganciclovir or foscarnet treatment.","date":"1996","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/8900310","citation_count":70,"is_preprint":false},{"pmid":"9725232","id":"PMC_9725232","title":"Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9725232","citation_count":69,"is_preprint":false},{"pmid":"2547869","id":"PMC_2547869","title":"IL-4 induces LFA-1 and LFA-3 expression on Burkitt's lymphoma cell lines. Requirement of additional activation by phorbol myristate acetate for induction of homotypic cell adhesions.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2547869","citation_count":68,"is_preprint":false},{"pmid":"34168659","id":"PMC_34168659","title":"CD58 Immunobiology at a Glance.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34168659","citation_count":65,"is_preprint":false},{"pmid":"1721039","id":"PMC_1721039","title":"New monoclonal antibodies in CD44 and CD58: their use to quantify CD44 and CD58 on normal human erythrocytes and to compare the distribution of CD44 and CD58 in human tissues.","date":"1991","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1721039","citation_count":65,"is_preprint":false},{"pmid":"14607753","id":"PMC_14607753","title":"Expression of CD58 in normal, regenerating and leukemic bone marrow B cells: implications for the detection of minimal residual disease in acute lymphocytic leukemia.","date":"2003","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/14607753","citation_count":63,"is_preprint":false},{"pmid":"7530239","id":"PMC_7530239","title":"Induction of ICAM-1 and LFA-3 by Tax1 of human T-cell leukemia virus type 1 and mechanism of down-regulation of ICAM-1 or LFA-1 in adult-T-cell-leukemia cell lines.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7530239","citation_count":62,"is_preprint":false},{"pmid":"27469079","id":"PMC_27469079","title":"CD2-CD58 interactions are pivotal for the activation and function of adaptive natural killer cells in human cytomegalovirus infection.","date":"2016","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27469079","citation_count":60,"is_preprint":false},{"pmid":"35728062","id":"PMC_35728062","title":"CD58 loss in tumor cells confers functional impairment of CAR T cells.","date":"2022","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/35728062","citation_count":56,"is_preprint":false},{"pmid":"1691936","id":"PMC_1691936","title":"Low expression of lymphocyte function-associated antigen (LFA)-1 and LFA-3 adhesion molecules is a common trait in Burkitt's lymphoma associated with and not associated with Epstein-Barr virus.","date":"1990","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1691936","citation_count":55,"is_preprint":false},{"pmid":"7686194","id":"PMC_7686194","title":"Immune modulation of adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) in human hepatocytic cell lines.","date":"1993","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/7686194","citation_count":54,"is_preprint":false},{"pmid":"10200255","id":"PMC_10200255","title":"Crystal structure of the CD2-binding domain of CD58 (lymphocyte function-associated antigen 3) at 1.8-A resolution.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10200255","citation_count":52,"is_preprint":false},{"pmid":"35881486","id":"PMC_35881486","title":"Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35881486","citation_count":50,"is_preprint":false},{"pmid":"7515920","id":"PMC_7515920","title":"CD58 (LFA-3) stimulation provides a signal for human isotype switching and IgE production distinct from CD40.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7515920","citation_count":50,"is_preprint":false},{"pmid":"11258789","id":"PMC_11258789","title":"CD58/LFA-3 and IL-12 provided by activated monocytes are critical in the in vitro expansion of CD56+ T cells.","date":"2001","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/11258789","citation_count":48,"is_preprint":false},{"pmid":"7688025","id":"PMC_7688025","title":"Mutational analysis of the CD2/CD58 interaction: the binding site for CD58 lies on one face of the first domain of human CD2.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7688025","citation_count":47,"is_preprint":false},{"pmid":"12668431","id":"PMC_12668431","title":"Forced detachment of the CD2-CD58 complex.","date":"2003","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12668431","citation_count":45,"is_preprint":false},{"pmid":"32589698","id":"PMC_32589698","title":"Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32589698","citation_count":44,"is_preprint":false},{"pmid":"1718801","id":"PMC_1718801","title":"Adhesion molecules in human islet beta-cells. De novo induction of ICAM-1 but not LFA-3.","date":"1991","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/1718801","citation_count":44,"is_preprint":false},{"pmid":"7681075","id":"PMC_7681075","title":"Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7681075","citation_count":43,"is_preprint":false},{"pmid":"1699592","id":"PMC_1699592","title":"Selective and non-selective loss of immunoregulatory molecules (HLA-A,B,C antigens and LFA-3) in transitional cell carcinoma.","date":"1990","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1699592","citation_count":43,"is_preprint":false},{"pmid":"7525842","id":"PMC_7525842","title":"Interaction between human CD2 and CD58 involves the major beta sheet surface of each of their respective adhesion domains.","date":"1994","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7525842","citation_count":43,"is_preprint":false},{"pmid":"24727892","id":"PMC_24727892","title":"CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24727892","citation_count":41,"is_preprint":false},{"pmid":"7685328","id":"PMC_7685328","title":"Differential expression and release of LFA-3 and ICAM-1 in human melanoma cell lines.","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7685328","citation_count":41,"is_preprint":false},{"pmid":"1723296","id":"PMC_1723296","title":"Dual function of recombinant human CD58: inhibition of T cell adhesion and activation via the CD2 pathway.","date":"1991","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1723296","citation_count":41,"is_preprint":false},{"pmid":"7530258","id":"PMC_7530258","title":"Human luteal cells express leukocyte functional antigen (LFA)-3.","date":"1995","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/7530258","citation_count":41,"is_preprint":false},{"pmid":"27467287","id":"PMC_27467287","title":"CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27467287","citation_count":40,"is_preprint":false},{"pmid":"1385151","id":"PMC_1385151","title":"Structural and functional epitopes of the human adhesion receptor CD58 (LFA-3).","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1385151","citation_count":39,"is_preprint":false},{"pmid":"11575926","id":"PMC_11575926","title":"Molecular dissection of the CD2-CD58 counter-receptor interface identifies CD2 Tyr86 and CD58 Lys34 residues as the functional \"hot spot\".","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11575926","citation_count":39,"is_preprint":false},{"pmid":"11591762","id":"PMC_11591762","title":"Endothelial cell costimulation of T cell activation through CD58-CD2 interactions involves lipid raft aggregation.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11591762","citation_count":39,"is_preprint":false},{"pmid":"17168569","id":"PMC_17168569","title":"Mechanisms of Cellular Avidity Regulation in CD2-CD58-Mediated T Cell Adhesion.","date":"2006","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/17168569","citation_count":39,"is_preprint":false},{"pmid":"8760789","id":"PMC_8760789","title":"Histamine selectively enhances human immunoglobulin E (IgE) and IgG4 production induced by anti-CD58 monoclonal antibody.","date":"1996","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8760789","citation_count":39,"is_preprint":false},{"pmid":"1372880","id":"PMC_1372880","title":"Elevated expression of ICAM1 (CD54) and minimal expression of LFA3 (CD58) in Epstein-Barr-virus-positive nasopharyngeal carcinoma cells.","date":"1992","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1372880","citation_count":37,"is_preprint":false},{"pmid":"1712347","id":"PMC_1712347","title":"Frequency of abnormal expression of HLA-A,B,C and HLA-DR molecules, invariant chain, and LFA-3 (CD58) in colorectal carcinoma and its impact on tumor recurrence.","date":"1991","source":"International journal of cancer. Supplement = Journal international du cancer. Supplement","url":"https://pubmed.ncbi.nlm.nih.gov/1712347","citation_count":37,"is_preprint":false},{"pmid":"2459195","id":"PMC_2459195","title":"Role of the LFA3-CD2 interaction in human specific B cell differentiation.","date":"1988","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2459195","citation_count":36,"is_preprint":false},{"pmid":"10357807","id":"PMC_10357807","title":"Functional glycan-free adhesion domain of human cell surface receptor CD58: design, production and NMR studies.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10357807","citation_count":36,"is_preprint":false},{"pmid":"7693485","id":"PMC_7693485","title":"A soluble form of the adhesion receptor CD58 (LFA-3) is present in human body fluids.","date":"1993","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7693485","citation_count":36,"is_preprint":false},{"pmid":"26194173","id":"PMC_26194173","title":"Alterations of the CD58 gene in classical Hodgkin lymphoma.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26194173","citation_count":35,"is_preprint":false},{"pmid":"3514752","id":"PMC_3514752","title":"Gene mapping and somatic cell hybrid analysis of the role of human lymphocyte function-associated antigen-3 (LFA-3) in CTL-target cell interactions.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3514752","citation_count":35,"is_preprint":false},{"pmid":"31962268","id":"PMC_31962268","title":"EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas.","date":"2020","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31962268","citation_count":33,"is_preprint":false},{"pmid":"7521361","id":"PMC_7521361","title":"CD59 costimulation of T cell activation. CD58 dependence and requirement for glycosylation.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7521361","citation_count":33,"is_preprint":false},{"pmid":"27337048","id":"PMC_27337048","title":"Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein-Protein Interaction.","date":"2016","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/27337048","citation_count":33,"is_preprint":false},{"pmid":"10220497","id":"PMC_10220497","title":"Polarized expression and function of the costimulatory molecule CD58 on human intestinal epithelial cells.","date":"1999","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/10220497","citation_count":32,"is_preprint":false},{"pmid":"1376653","id":"PMC_1376653","title":"The expression and role in T cell adhesion of LFA-3 and ICAM-2 on human thyroid cells.","date":"1992","source":"Clinical immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/1376653","citation_count":32,"is_preprint":false},{"pmid":"30763849","id":"PMC_30763849","title":"Decreased erythrocyte CD44 and CD58 expression link e-waste Pb toxicity to changes in erythrocyte immunity in preschool children.","date":"2019","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/30763849","citation_count":30,"is_preprint":false},{"pmid":"29904386","id":"PMC_29904386","title":"Costimulatory Function of Cd58/Cd2 Interaction in Adaptive Humoral Immunity in a Zebrafish Model.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29904386","citation_count":30,"is_preprint":false},{"pmid":"35296559","id":"PMC_35296559","title":"Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35296559","citation_count":30,"is_preprint":false},{"pmid":"21755948","id":"PMC_21755948","title":"Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58.","date":"2011","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21755948","citation_count":29,"is_preprint":false},{"pmid":"36516256","id":"PMC_36516256","title":"PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36516256","citation_count":27,"is_preprint":false},{"pmid":"7525717","id":"PMC_7525717","title":"Polyclonal B cell activation induced by herpesvirus saimiri-transformed human CD4+ T cell clones. Role for membrane TNF-alpha/TNF-alpha receptors and CD2/CD58 interactions.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7525717","citation_count":27,"is_preprint":false},{"pmid":"24655566","id":"PMC_24655566","title":"CD58 polymorphisms associated with the risk of neuromyelitis optica in a Korean population.","date":"2014","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24655566","citation_count":26,"is_preprint":false},{"pmid":"15762287","id":"PMC_15762287","title":"CD58 expression decreases as nonmalignant B cells mature in bone marrow and is frequently overexpressed in adult and pediatric precursor B-cell acute lymphoblastic leukemia.","date":"2005","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15762287","citation_count":26,"is_preprint":false},{"pmid":"15110076","id":"PMC_15110076","title":"Immunotherapeutic effects of T11TS/S-LFA3 against nitrosocompound mediated neural genotoxicity.","date":"2004","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/15110076","citation_count":25,"is_preprint":false},{"pmid":"7519509","id":"PMC_7519509","title":"Expression of adhesion molecules CD11/CD18 (Leu-CAMs, beta 2-integrins), CD54 (ICAM-1) and CD58 (LFA-3) in B-chronic lymphocytic leukemia.","date":"1994","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/7519509","citation_count":25,"is_preprint":false},{"pmid":"9691200","id":"PMC_9691200","title":"MHC class II ligation induces CD58 (LFA-3)-mediated adhesion in human T cells.","date":"1998","source":"Experimental and clinical immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9691200","citation_count":25,"is_preprint":false},{"pmid":"1722705","id":"PMC_1722705","title":"Cell surface expression of ICAM-1 (CD54) and LFA-3 (CD58), two adhesion molecules, is up-regulated on bone marrow leukemic blasts after in vivo administration of high-dose recombinant interleukin-2.","date":"1991","source":"Journal of immunotherapy : official journal of the Society for Biological Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/1722705","citation_count":24,"is_preprint":false},{"pmid":"10470114","id":"PMC_10470114","title":"Differential expression of adhesion molecules (CD44, ICAM-1 and LFA-3) in cancer cells grown in monolayer or as multicellular spheroids.","date":"1999","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10470114","citation_count":24,"is_preprint":false},{"pmid":"14572797","id":"PMC_14572797","title":"Red blood cells promote survival and cell cycle progression of human peripheral blood T cells independently of CD58/LFA-3 and heme compounds.","date":"2003","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14572797","citation_count":24,"is_preprint":false},{"pmid":"38635903","id":"PMC_38635903","title":"CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma.","date":"2024","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38635903","citation_count":23,"is_preprint":false},{"pmid":"38589927","id":"PMC_38589927","title":"HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38589927","citation_count":23,"is_preprint":false},{"pmid":"8907282","id":"PMC_8907282","title":"Expression of glycosyl-phosphatidylinositol-linked glycoproteins in blood cells from paroxysmal nocturnal haemoglobinuria patients: a flow cytometry study using CD55, CD58 and CD59 monoclonal antibodies.","date":"1996","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/8907282","citation_count":23,"is_preprint":false},{"pmid":"11157851","id":"PMC_11157851","title":"Effects of co-stimulation by CD58 on human T cell cytokine production: a selective cytokine pattern with induction of high IL-10 production.","date":"2001","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11157851","citation_count":23,"is_preprint":false},{"pmid":"29773030","id":"PMC_29773030","title":"T Cell Activation Pathways: B7, LFA-3, and ICAM-1 Shape Unique T Cell Profiles.","date":"2017","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29773030","citation_count":22,"is_preprint":false},{"pmid":"8550244","id":"PMC_8550244","title":"Expression of leukocyte cell adhesion molecules on gastric carcinomas: possible involvement of LFA-3 expression in the development of distant metastases.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8550244","citation_count":22,"is_preprint":false},{"pmid":"7584496","id":"PMC_7584496","title":"The effects of an immunomodulatory LFA3-IgG1 fusion protein on nonhuman primates.","date":"1994","source":"Therapeutic immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7584496","citation_count":22,"is_preprint":false},{"pmid":"2471647","id":"PMC_2471647","title":"A monoclonal antibody to LFA-3, the CD2 ligand, specifically immobilizes major histocompatibility complex proteins.","date":"1989","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2471647","citation_count":22,"is_preprint":false},{"pmid":"17172599","id":"PMC_17172599","title":"Impact of salt bridges on the equilibrium binding and adhesion of human CD2 and CD58.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17172599","citation_count":21,"is_preprint":false},{"pmid":"8958918","id":"PMC_8958918","title":"CD2-CD58 interaction and the control of T-cell interleukin-12 responsiveness. Adhesion molecules link innate and acquired immunity.","date":"1996","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8958918","citation_count":20,"is_preprint":false},{"pmid":"12798307","id":"PMC_12798307","title":"A recombinant vector expressing transgenes for four T-cell costimulatory molecules (OX40L, B7-1, ICAM-1, LFA-3) induces sustained CD4+ and CD8+ T-cell activation, protection from apoptosis, and enhanced cytokine production.","date":"2003","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12798307","citation_count":20,"is_preprint":false},{"pmid":"23530775","id":"PMC_23530775","title":"Immunosuppression by co-stimulatory molecules: inhibition of CD2-CD48/CD58 interaction by peptides from CD2 to suppress progression of collagen-induced arthritis in mice.","date":"2013","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/23530775","citation_count":19,"is_preprint":false},{"pmid":"7503960","id":"PMC_7503960","title":"Enhanced expression of LFA-3 on human T-cell lines and leukemic cells carrying human T-cell-leukemia virus type 1.","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7503960","citation_count":19,"is_preprint":false},{"pmid":"25143920","id":"PMC_25143920","title":"Immunoregulatory T cells, LFA-3 and HLA-DR in autoimmune thyroid diseases.","date":"2014","source":"Indian journal of endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25143920","citation_count":19,"is_preprint":false},{"pmid":"12716291","id":"PMC_12716291","title":"Preclinical Changes in Immunoreactivity and Cellular Architecture during the Progressive Development of Intracranial Neoplasms and an Immunotherapeutic Schedule with a Novel Biological Response Modifier, the T11TS / S-LFA3.","date":"2002","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/12716291","citation_count":18,"is_preprint":false},{"pmid":"9574540","id":"PMC_9574540","title":"The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 associate with protein kinases.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9574540","citation_count":18,"is_preprint":false},{"pmid":"15345303","id":"PMC_15345303","title":"A novel, rapid and sensitive heterotypic cell adhesion assay for CD2-CD58 interaction, and its application for testing inhibitory peptides.","date":"2004","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/15345303","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51150,"output_tokens":8746,"usd":0.14232,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18850,"output_tokens":4986,"usd":0.10945,"stage2_stop_reason":"end_turn"},"total_usd":0.25177,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1987,\n      \"finding\": \"CD2 (LFA-2/T11) directly binds LFA-3 (CD58) on cell surfaces, mediating T cell adhesion to lymphoid cells; purified CD2 inhibits T-cell rosetting with human erythrocytes and is absorbed by sheep erythrocytes expressing LFA-3, establishing CD58 as the natural ligand for CD2.\",\n      \"method\": \"Ligand binding with purified protein, rosette inhibition assay, absorption experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein binding demonstrated, replicated across multiple labs and confirmed with reciprocal inhibition assays\",\n      \"pmids\": [\"2951597\", \"3102675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"LFA-3 (CD58) is widely distributed on hematopoietic and non-hematopoietic tissues; anti-LFA-3 monoclonal antibodies block CTL-mediated cytolysis by binding to target cells (not effector cells), indicating CD58 functions on target cells in CTL interactions.\",\n      \"method\": \"Monoclonal antibody generation and 51Cr-release cytotoxicity blocking assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent labs confirmed target-cell-side function of LFA-3 in CTL killing\",\n      \"pmids\": [\"6345670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Human CD2 binds CD58 with very low affinity (Kd 9–22 µM) and an extremely fast dissociation rate (koff ≥ 4 s⁻¹); CD2 does not detectably bind CD48 or CD59 under the same conditions, establishing CD58 as the primary high-specificity ligand for human CD2.\",\n      \"method\": \"Surface plasmon resonance (BIAcore) with soluble recombinant ectodomains\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous biophysical measurement with recombinant proteins, defining quantitative kinetic parameters\",\n      \"pmids\": [\"7520278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Crystal structure of the CD2-binding domain of CD58 at 1.8-Å resolution reveals an Ig superfamily V-set topology shared with CD2; the ligand-binding surface of CD58 is the highly acidic AGFCC'C\\\" beta-sheet face; mutations that disrupt CD2 binding map to this surface, and the interface lacks strong shape complementarity, suggesting electrostatic complementarity drives specificity.\",\n      \"method\": \"X-ray crystallography at 1.8 Å with functional mutagenesis validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis in a single study\",\n      \"pmids\": [\"10200255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The CD58-binding site on CD2 maps to the major AGFCC'C\\\" beta-sheet face of domain 1; substitution of residues K34, E36 (strand C), R48, K49 (strand C'), and K91, N92 (FG loop) abrogates rosetting with human and sheep erythrocytes, demonstrating that these charged residues are critical for CD2–CD58 interaction.\",\n      \"method\": \"Site-directed mutagenesis of CD2 combined with rosetting assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with functional readout, consistent with structural data\",\n      \"pmids\": [\"7688025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The CD58 binding surface on CD2 involves residues on the C, C', and CC' loop strands; mutating charged residues E25, K29, K30 (C strand), E37 (C' strand), K32, D33, K34 (CC' loop), and K87 (G strand) of CD58 reduces CD2 binding, establishing that CD2–CD58 interaction involves the major beta-sheet surface of each adhesion domain in a 'handshake' orientation.\",\n      \"method\": \"Site-directed mutagenesis of CD58 combined with cell adhesion and rosetting assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of CD58, confirmed with multiple binding assays\",\n      \"pmids\": [\"7525842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NMR solution structure of a glycan-free CD58 adhesion domain confirms binding to CD2 involves the GFCC'C\\\" faces of both molecules; chemical shift perturbations in NMR titration localize the binding site to C, C', and C\\\" strands and loops of CD58.\",\n      \"method\": \"NMR spectroscopy with titration experiments using recombinant CD58 adhesion domain\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional binding validation in same study\",\n      \"pmids\": [\"10357807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The functional hot spot of the CD2–CD58 interface is defined by CD2 Tyr86 and CD58 Lys34; alanine scanning of salt-bridge residues shows D31A, D32A, K34A, K43A, R48A reduce affinity 47–127-fold, while Y86A reduces affinity ~1000-fold; crystal structure analysis shows CD2 Y86 makes hydrophobic contact with the aliphatic chain of CD58 K34.\",\n      \"method\": \"Isothermal titration calorimetry with alanine-scanning mutagenesis; crystal structure analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative calorimetry and structural analysis in single study with systematic mutagenesis\",\n      \"pmids\": [\"11575926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD58 engagement of CD2 on T cells activates AP-1, NF-AT, NF-κB, and NF-IL-2 transcriptional pathways and promotes lipid raft aggregation on T cells, amplifying TCR signaling; anti-CD2 antibodies block all these effects and EC-induced raft aggregation.\",\n      \"method\": \"Luciferase reporter assays for transcription factors, lipid raft aggregation assay with CD2 blocking antibodies in CD58-expressing endothelial cell co-cultures\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in single lab, mechanistic pathway analysis with blocking controls\",\n      \"pmids\": [\"11591762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"LFA-3 activates T cells via CD2 under appropriate conditions, but this activation requires both cell surface expression of CD3/TCR complex and a functional antigen receptor pathway; a CD3-negative CD2+ Jurkat mutant fails to respond to LFA-3 plus anti-CD2, and TCR-β chain transfection restores responsiveness.\",\n      \"method\": \"Genetic reconstitution in Jurkat mutants; calcium flux and phosphatidylinositol hydrolysis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by reconstitution with multiple biochemical readouts, replicated across multiple mutant lines\",\n      \"pmids\": [\"2459194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"GPI-anchored LFA-3 (CD58) diffuses laterally in membranes with a coefficient approaching phospholipids, whereas transmembrane LFA-3 is immobile; GPI-anchored LFA-3 supports faster and more efficient adhesion strengthening with CD2+ T cells at low site densities due to receptor accumulation in the contact zone.\",\n      \"method\": \"Reconstituted planar lipid bilayers with two LFA-3 isoforms; static and laminar flow adhesion assays; fluorescence recovery measurements\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted system with controlled receptor density, multiple assay formats, quantitative kinetic measurements\",\n      \"pmids\": [\"1717480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Both the GPI-anchored and transmembrane forms of CD58 associate with protein kinase(s); crosslinking either isoform with immobilized anti-CD58 antibodies induces extensive tyrosine phosphorylation and TNF-alpha secretion in B cells, establishing CD58's role in signal transduction independent of anchor type.\",\n      \"method\": \"Immunoprecipitation kinase assay; comparison of JY variant cells expressing only one isoform; anti-CD58 crosslinking with tyrosine phosphorylation readout\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-immunoprecipitation with kinase assay, isoform-specific variant cell lines\",\n      \"pmids\": [\"9574540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Ligation of B cell CD58 by CD2 or by anti-CD58 monoclonal antibody provides an IL-4-dependent signal that drives IgE class switch recombination (inducing productive ε transcripts and IgE protein production) distinct from the CD40 pathway; direct CD2 involvement was confirmed by co-culture with CD2-transfected T hybridoma cells.\",\n      \"method\": \"Purified B cells co-stimulated with IL-4 and anti-CD58 mAb; RT-PCR for ε transcripts; ELISA for IgE; CD40-Fc fusion protein competition; CD2-transfected hybridoma co-culture\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including genetic (CD2 transfectants), blocking antibodies, and molecular (transcript) readouts\",\n      \"pmids\": [\"7515920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD2–CD58 interaction between T cells and monocytes specifically regulates T cell responsiveness to IL-12; CHO cells expressing CD58 at monocyte-equivalent levels restore IL-12 responsiveness to APC-depleted T cells, whereas CD48-expressing CHO cells (low avidity CD2 ligand) do not, demonstrating that high-avidity CD58–CD2 ligation is required for IL-12 co-signaling.\",\n      \"method\": \"APC-depletion experiments; CD58-transfected CHO cell reconstitution; proliferation assays; anti-CD2/CD58 blocking antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution with CHO transfectants, specificity shown by CD48 negative control, multiple functional readouts\",\n      \"pmids\": [\"8757306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"TCR stimulation rapidly upregulates CD2 avidity for CD58; this regulation requires both protein tyrosine kinase activity and protein kinase C activity, and requires the carboxyl-terminal asparagine of the CD2 cytoplasmic domain; cAMP elevation also upregulates CD2 avidity through the same structural element.\",\n      \"method\": \"CD2 avidity assay (cell binding to purified CD58 and SRBC rosetting); kinase inhibitors; CD2 cytoplasmic domain single amino acid substitution mutants in Jurkat hybridomas\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis of CD2 cytoplasmic domain, multiple pharmacological inhibitors, functional binding readout\",\n      \"pmids\": [\"7681075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"T cell activation increases CD2 surface expression 1.5-fold and the 2D affinity of CD2 for CD58 2.5-fold; combined T cell activation and CD2 ligation to CD58 decreases the laterally mobile fraction of CD2, consistent with cytoskeletal immobilization at the contact site to strengthen T cell–APC adhesion.\",\n      \"method\": \"Fluorescence recovery after photobleaching (FRAP); quantitative surface receptor measurements; 2D affinity measurements on supported lipid bilayers\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative biophysical measurements, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17168569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Steered molecular dynamics simulations show that at slow loading rates CD2 and CD58 separate before unfolding; salt bridges primarily determine tensile strength of the CD2–CD58 bond, and the order of salt bridge rupture correlates with their position relative to the force vector; simulation results correlate with cell aggregation and equilibrium binding data from site-directed mutagenesis.\",\n      \"method\": \"Steered molecular dynamics simulations; correlation with published mutagenesis data\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — computational simulation with validation against experimental mutagenesis data; single study\",\n      \"pmids\": [\"12668431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Quantitative surface force apparatus measurements confirm that single charge mutations at CD2 D31, K41, K51, K91 alter both solution-phase binding kinetics (SPR) and cell adhesion strength for the CD2–CD58 interaction, validating the role of specific salt bridges in adhesion.\",\n      \"method\": \"Surface plasmon resonance; surface force apparatus adhesion measurements with CD2 charge mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal quantitative methods, single lab\",\n      \"pmids\": [\"17172599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Anti-LFA-3 monoclonal antibody crosslinks LFA-3 and induces lateral immobilization of class I and class II MHC proteins in the plasma membrane of B cells, suggesting that CD2 binding to LFA-3 on target cells may immobilize and concentrate MHC molecules at the T cell–target cell interface.\",\n      \"method\": \"Fluorescence photobleaching recovery (FPR) on JY B cells; bivalent vs. monovalent fluorescent antibody comparison\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative membrane mobility assay with multiple molecular targets and controls, single lab\",\n      \"pmids\": [\"2471647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NK cell lysis of CMV-infected fibroblasts correlates with upregulation of LFA-3 (CD58) on infected cells, not with MHC class I downregulation; viral strains that upregulate LFA-3 render cells susceptible to NK killing, while strains that downregulate LFA-3 make cells resistant; a minimum of 29,000–71,000 LFA-3 molecules per target are required for NK susceptibility.\",\n      \"method\": \"NK cytotoxicity assay with multiple CMV strains; flow cytometry for LFA-3 and MHC I; quantitative threshold analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple viral strains used as natural genetic variation, quantitative threshold established, consistent across different cell types\",\n      \"pmids\": [\"9725232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Coexpression of CD58 (or CD48) with ICAM-1 on target cells enhances adhesion of resting NK cells beyond that mediated by ICAM-1 alone, in the absence of cytokine priming; receptors for LFA-3 on resting NK cells strengthen LFA-1–mediated adhesion.\",\n      \"method\": \"Drosophila cells expressing defined combinations of human ligands; NK cell adhesion assays with kinase inhibitors\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstituted system with Drosophila cells expressing defined ligands, single lab\",\n      \"pmids\": [\"12496412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM6 is required for CD58 protein stability; loss of CD58 leads to increased PD-L1 protein stabilization because CD58 and PD-L1 compete for CMTM6 binding, which determines their rate of endosomal recycling versus lysosomal degradation; intact cancer cell CD58 expression and ligation of CD2 is required for anti-tumor immunity and predicts checkpoint blockade response.\",\n      \"method\": \"CRISPR-Cas9 screens; proteomics; patient-derived co-cultures; humanized mouse models; single-cell RNA-seq of patient biopsies; co-immunoprecipitation for CMTM6 interactions\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, proteomics, co-IP, in vivo models, patient samples) in one study\",\n      \"pmids\": [\"37327789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EZH2 epigenetically silences CD58 expression in B-cell lymphoma cells through H3K27 trimethylation at the CD58 promoter; EZH2 inhibitors (EPZ6438, GSK126) restore CD58 expression by demethylating H3K27me3 at the CD58 locus and enhance T/NK cell IFN-γ production against lymphoma cells.\",\n      \"method\": \"Epigenetic inhibitor library screen; ChIP for H3K27me3 at CD58 promoter; flow cytometry; IFN-γ functional assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates H3K27me3 at promoter, functional rescue with pharmacological inhibitors, single lab\",\n      \"pmids\": [\"31962268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAX5 is the key transcriptional activator of CD58 in B-ALL; PAX5 P80R mutation disrupts a PAX5-driven enhancer at the CD58 locus, reducing CD58 expression; loss of CD58 confers resistance to blinatumomab by abolishing blinatumomab-induced T cell activation; identified by genome-wide CRISPR screen followed by transcription factor screen of 1639 genes.\",\n      \"method\": \"Genome-wide CRISPR screen; transcription factor CRISPR screen; genome editing to introduce/correct PAX5 P80R; ChIP/ATAC-seq for enhancer; co-culture cytotoxicity assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen validated by genome editing, epigenomic mapping, and functional assays in single study\",\n      \"pmids\": [\"36516256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD58 inhibits JAK2/STAT1 pathway activity by activating the LYN/CD22/SHP1 axis; loss of CD58 in DLBCL leads to elevated PDL1 and IDO expression through this pathway, contributing to immune evasion; direct CD58–CD2 costimulation combined with anti-PDL1 or IDO inhibitor sensitizes CD58-deficient DLBCL to CAR-T therapy.\",\n      \"method\": \"Targeted NGS, RNA-seq, WES, scRNA-seq; co-IP for pathway components; pharmacological inhibitor combinations; CAR-T cytotoxicity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for LYN/CD22/SHP1 axis, multiple orthogonal analyses, single lab\",\n      \"pmids\": [\"38635903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA4 upregulation increases ALKBH5 protein stability; ALKBH5 (m6A demethylase) decreases CD58 mRNA in gastric cancer cells through m6A methylation regulation, reducing CD8+ T cell cytotoxicity and activating PD1/PDL1 axis.\",\n      \"method\": \"Co-immunoprecipitation; meRIP (m6A RNA immunoprecipitation); co-culture cytotoxicity assay; HSPA4 overexpression/knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and meRIP establish mechanism, functional cytotoxicity readout, single lab\",\n      \"pmids\": [\"38589927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CD2 expression on a murine T cell hybridoma greatly enhances T cell responsiveness to antigen in an LFA-3-dependent manner; a CD2 mutant lacking the mAb 9.6 epitope loses both enhanced antigen responsiveness and LFA-3-driven activation but retains activation by anti-CD2 antibody pairs, indicating the CD2–LFA-3 interaction requires an intact CD2 extracellular epitope.\",\n      \"method\": \"cDNA expression of wild-type and mutant CD2 in murine T cell hybridoma; IL-2 production assays; anti-CD2 and anti-LFA-3 blocking antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution of human CD2 in murine cells with epitope-loss mutant, functional IL-2 production readout\",\n      \"pmids\": [\"2448792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Genome-wide CRISPR/Cas9 screen identifies CD58 loss as a mechanism of tumor resistance to CAR T cell therapy; CD58-deficient tumor cells form suboptimal immunological synapses with CAR T cells, impairing CAR T cell expansion, degranulation, cytokine secretion, and cytotoxicity in vitro and in vivo.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen; CD58 knockout validation; in vitro CAR T functional assays; in vivo xenograft model; immunological synapse analysis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screen validated by targeted KO, multiple functional readouts, in vivo confirmation\",\n      \"pmids\": [\"35728062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD58/CD2 axis is the primary costimulatory pathway in CD28-negative CD8+ T cells; CD58 on APCs (including dendritic cells) engages CD2 on CD28⁻CD8⁺ T cells to costimulate proliferation, cytokine production, and effector function; CD2 engagement amplifies TCR signals in this subset.\",\n      \"method\": \"Blocking anti-CD58 mAb in allogeneic DC assays; viral antigen recall responses; T cell proliferation and cytokine assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking experiments with multiple readouts, single lab\",\n      \"pmids\": [\"26041540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The protective rs2300747(G) allele of CD58 is associated with dose-dependent increases in CD58 mRNA expression in lymphoblastic cell lines and PBMCs; increased CD58 expression upregulates FoxP3 expression through engagement of CD2, enhancing function of CD4+CD25high regulatory T cells.\",\n      \"method\": \"Fine mapping and resequencing; dose-dependent mRNA expression analysis; functional CD58–CD2 engagement assay measuring FoxP3 induction\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic variant linked to expression and functional outcome via CD2 engagement, single lab\",\n      \"pmids\": [\"19237575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD58 is expressed constitutively on the basolateral surface of polarized intestinal epithelial cells (but not CD80 or CD86); this basolateral CD58 acts as the costimulatory molecule mediating HLA class II antigen presentation to CD4+ T cells, as anti-CD58 antibodies block IEC-stimulated T cell proliferation while anti-CD80/CD86 do not.\",\n      \"method\": \"Flow cytometry; confocal microscopy; vectorial biotinylation to determine polarized localization; antibody blocking of T cell proliferation\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by vectorial biotinylation linked to functional consequence, single lab\",\n      \"pmids\": [\"10220497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CMV infection directly upregulates LFA-3 and ICAM-1 cell-surface expression on fibroblasts; this is a direct viral effect (not cytokine-mediated) requiring infectious virus; LFA-3 accumulates in perinuclear granules in infected cells vs. diffuse cytoplasmic distribution in uninfected cells.\",\n      \"method\": \"Flow cytometry; neutralizing antibody experiments against candidate cytokines; UV-inactivated virus controls; confocal scanning laser microscopy; immunofluorescence\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple controls (UV-inactivated virus, cytokine neutralization), imaging-confirmed localization change, single lab\",\n      \"pmids\": [\"7682988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD2–CD58 binding is required for activation and effector functions of adaptive (NKG2C+CD57+) NK cells in response to HCMV-infected cells; antibody blockade of CD2 or CD58 largely blocks upregulation of activation markers (CD69, CD25, HLA-DR) and production of IFN-γ and TNF-α specifically in adaptive NK cells.\",\n      \"method\": \"Co-culture of human PBMCs with HCMV-infected fibroblasts; CD2/CD58 blocking antibodies; flow cytometry for activation markers and intracellular cytokines\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with multiple readouts, subset-specific analysis, single lab\",\n      \"pmids\": [\"27469079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD58 expression on Hodgkin lymphoma Reed-Sternberg cells determines extent of T cell rosette formation and T cell activation; CD58 knockout or CD2 blockade reduces both rosetting and T cell activation; proximity ligation assays in primary HL tissue confirm CD2–CD58 interactions at the immunological synapse.\",\n      \"method\": \"CD58 knockout by CRISPR (CIITA KO for HLA-II comparison); rosetting co-culture model; proximity ligation assay on primary tissue; flow cytometry for T cell activation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with functional readout, validated in primary patient tissue by proximity ligation assay\",\n      \"pmids\": [\"32589698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD58 promotes self-renewal of colorectal tumor-initiating cells by upregulating the Wnt/β-catenin pathway through degradation of Dickkopf 3 (DKK3); CD58 knockdown impairs sphere formation and tumor growth; CD58–DKK3 interaction identified by co-immunoprecipitation and western blotting.\",\n      \"method\": \"cDNA GeneChip; flow cytometry; sphere formation assay; xenograft in vivo; co-immunoprecipitation and western blot for DKK3 degradation; lentiviral CD58 knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional pathway validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"24727892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MHC class II ligation induces homotypic T cell adhesion that is almost completely inhibited by anti-CD58 antibody and partly by anti-CD2 antibody, establishing that CD58–CD2 interaction is required for class-II-induced T cell aggregation; demonstrated in β2-integrin-deficient T cells confirming β2-integrin independence.\",\n      \"method\": \"Cell aggregation assay with blocking monoclonal antibodies in β2-integrin-negative (LAD patient) T cell lines\",\n      \"journal\": \"Experimental and clinical immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic variant cell lines (LAD patient), multiple antibody blockades, single lab\",\n      \"pmids\": [\"9691200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Soluble CD58 (sCD58) is present as a natural protein in human serum, urine, and cell culture supernatants; it forms noncovalent homotrimers (~118–166 kDa by gel filtration) and at high concentrations binds to CD2+ T cells and inhibits rosette formation, suggesting sCD58 can suppress CD2–CD58-mediated adhesion in vivo.\",\n      \"method\": \"ELISA; SDS-PAGE and Western blotting; gel filtration; T cell rosette inhibition assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with functional inhibition assay, single lab\",\n      \"pmids\": [\"7693485\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD58 (LFA-3) is a broadly expressed Ig-superfamily cell adhesion and costimulatory molecule that functions as the primary high-specificity ligand for CD2 on T and NK cells, binding through complementary charged beta-sheet surfaces (with CD2 Tyr86–CD58 Lys34 as the functional hot spot) with very low affinity and fast kinetics; it promotes T/NK cell adhesion, immunological synapse formation, and costimulatory signaling by amplifying TCR-proximal signals via lipid raft aggregation, regulates T cell IL-12 responsiveness, drives IgE class switching, and is epigenetically controlled by EZH2 (H3K27me3) and transcriptionally activated by PAX5; CD58 protein stability is maintained by CMTM6, which also controls PD-L1 stability through competitive recycling, and CD58 loss in cancer cells promotes immune evasion by forming suboptimal immunological synapses, stabilizing PD-L1, and activating IDO through the LYN/CD22/SHP1 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD58 (LFA-3) is a broadly distributed immunoglobulin-superfamily cell-surface adhesion and costimulatory molecule that serves as the principal high-specificity ligand for CD2 on T and NK cells, governing the formation and quality of the immunological synapse [#0, #2]. The CD58 adhesion domain is a V-set Ig fold whose highly acidic AGFCC'C\\\" beta-sheet face docks against the equivalent surface of CD2 in a charge-complementary \\\"handshake\\\"; the interaction is of very low affinity (Kd ~9-22 µM) with extremely fast dissociation kinetics, with electrostatic salt bridges driving specificity and the CD2 Tyr86-CD58 Lys34 contact acting as the dominant energetic hot spot [#2, #3, #5, #6, #7]. By engaging CD2, CD58 on antigen-presenting and target cells amplifies TCR-proximal signaling through lipid-raft aggregation and activation of AP-1, NF-AT, NF-κB and NF-IL-2 pathways, but this costimulation requires an intact CD3/TCR complex [#8, #9]. CD58 functions on the target/APC side of cytolytic and adhesive interactions: it supports CTL killing, MHC-class-II-driven T cell costimulation and adhesion, IL-12 responsiveness, IgE class switching in B cells, and NK cell activation against virally infected targets, and it is the primary costimulatory pathway for CD28-negative CD8+ T cells [#1, #8, #12, #13, #19, #28, #35]. CD58 surface levels are set at multiple regulatory layers: PAX5 transcriptionally activates a CD58 enhancer, EZH2-mediated H3K27me3 silences the locus, ALKBH5-dependent m6A regulation destabilizes its mRNA, and CMTM6 stabilizes the CD58 protein by controlling its endosomal recycling versus lysosomal degradation in competition with PD-L1 [#21, #22, #23, #25]. Loss of CD58 is a recurrent mechanism of tumor immune evasion: it produces suboptimal immunological synapses that impair CAR-T and endogenous T/NK effector function, stabilizes PD-L1, and activates IDO via the LYN/CD22/SHP1 axis, and CD58 status predicts response to immune checkpoint and immunotherapy [#21, #24, #27, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1983,\n      \"claim\": \"Established that CD58 acts on the target-cell side of cytolytic interactions, reframing it from a generic surface antigen to a functional partner in immune effector recognition.\",\n      \"evidence\": \"Anti-LFA-3 monoclonal antibody blocking of CTL-mediated cytolysis in 51Cr-release assays, mapping function to target cells\",\n      \"pmids\": [\"6345670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular binding partner of CD58 not yet identified\", \"Mechanism of how CD58 promotes killing not defined\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Identified CD2 as the direct binding partner of CD58, defining the receptor-ligand axis underlying T cell adhesion to lymphoid and target cells.\",\n      \"evidence\": \"Purified-protein ligand binding, rosette inhibition, and erythrocyte absorption experiments\",\n      \"pmids\": [\"2951597\", \"3102675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity and kinetics not quantified\", \"Structural basis of recognition unknown\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Showed that CD58-CD2 engagement requires the antigen-receptor machinery to deliver activation signals, linking the adhesion axis to TCR-dependent T cell activation rather than independent signaling.\",\n      \"evidence\": \"Genetic reconstitution of CD3-negative Jurkat mutants with TCR-beta and CD2 epitope-loss mutants, with calcium flux and PI hydrolysis readouts\",\n      \"pmids\": [\"2459194\", \"2448792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling intermediates not mapped\", \"Quantitative contribution of CD58 versus TCR signal not separated\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Quantified the CD2-CD58 interaction as very-low-affinity and fast-dissociating and established CD58 as the high-specificity ligand over CD48/CD59, explaining the kinetics that permit rapid, transient adhesion.\",\n      \"evidence\": \"Surface plasmon resonance with soluble recombinant ectodomains\",\n      \"pmids\": [\"7520278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface not resolved\", \"How fast kinetics support stable synapse adhesion unresolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the molecular interface as the charged AGFCC'C\\\" beta-sheet faces of both partners, providing a structural rationale for electrostatically driven specificity.\",\n      \"evidence\": \"Reciprocal site-directed mutagenesis of CD2 and CD58 charged residues with rosetting and adhesion assays\",\n      \"pmids\": [\"7688025\", \"7525842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Energetic hierarchy of individual contacts not yet established\", \"No high-resolution structure of the complex interface\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the CD58 adhesion domain structure, confirming a V-set Ig fold sharing topology with CD2 and an acidic ligand-binding face with poor shape complementarity, supporting an electrostatically driven recognition model.\",\n      \"evidence\": \"1.8-Å X-ray crystallography and NMR solution structure with mutagenesis and titration validation\",\n      \"pmids\": [\"10200255\", \"10357807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full co-complex thermodynamics not yet measured\", \"Role of glycosylation in vivo not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Pinpointed CD2 Tyr86-CD58 Lys34 as the dominant energetic hot spot, refining the binding model from uniformly distributed electrostatics to a defined hydrophobic anchor amid salt bridges.\",\n      \"evidence\": \"Isothermal titration calorimetry with alanine-scanning mutagenesis and crystal structure analysis\",\n      \"pmids\": [\"11575926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hot spot contribution to physiological adhesion strength not directly tested at the cell level here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked CD58-CD2 engagement to defined transcriptional programs and membrane reorganization, establishing CD58 as a costimulus that amplifies TCR signaling via lipid raft aggregation.\",\n      \"evidence\": \"Luciferase reporters for AP-1/NF-AT/NF-κB/NF-IL-2 and lipid raft aggregation assays with CD2 blocking antibodies in endothelial co-cultures\",\n      \"pmids\": [\"11591762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional pathway analysis\", \"Direct molecular link between CD2 engagement and raft coalescence not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected molecular binding properties to physical adhesion mechanics, showing salt bridges set the tensile strength of the bond and that activation tunes CD2 2D affinity and mobility to strengthen contact.\",\n      \"evidence\": \"Steered molecular dynamics, surface force apparatus, SPR, and FRAP on supported bilayers with CD2 charge mutants\",\n      \"pmids\": [\"12668431\", \"17172599\", \"17168569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational and biophysical models from single labs\", \"In vivo relevance of force-dependent rupture not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrated that CD58 signals beyond adhesion, driving IL-4-dependent IgE class switching and IL-12 responsiveness, broadening its role into B cell and T cell effector programming.\",\n      \"evidence\": \"Anti-CD58/CD2 ligation of B cells with epsilon transcript and IgE readouts; CD58-transfected CHO reconstitution of IL-12 responsiveness with CD48 negative control\",\n      \"pmids\": [\"7515920\", \"8757306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates downstream of CD58 ligation not mapped\", \"Whether B cell CD58 signals cell-autonomously versus via CD2 partner cell unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established CD58 as a determinant of NK-mediated immunity against viral infection, with a quantitative surface-density threshold governing target susceptibility.\",\n      \"evidence\": \"NK cytotoxicity assays across CMV strains with flow cytometry quantification of LFA-3 density\",\n      \"pmids\": [\"9725232\", \"7682988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CMV upregulates CD58 not defined\", \"Receptor on NK cells (CD2) contribution not formally isolated in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified transcriptional and epigenetic control of CD58 expression, showing PAX5 activates and EZH2-mediated H3K27me3 silences the locus, defining mechanisms that set CD58 surface abundance.\",\n      \"evidence\": \"Epigenetic inhibitor screen with ChIP for H3K27me3 and IFN-γ rescue; genome-wide and transcription-factor CRISPR screens with PAX5 P80R editing and ATAC/ChIP enhancer mapping\",\n      \"pmids\": [\"31962268\", \"36516256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between PAX5 and EZH2 control not integrated\", \"Tissue specificity of these regulatory mechanisms not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed post-translational control of CD58 by CMTM6, coupling CD58 protein stability to PD-L1 stability through competitive endosomal recycling and providing a mechanistic link between CD58 loss and checkpoint resistance.\",\n      \"evidence\": \"CRISPR screens, proteomics, co-IP, patient-derived co-cultures, and humanized mouse models\",\n      \"pmids\": [\"37327789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CMTM6 competition between CD58 and PD-L1 not resolved\", \"Whether other CMTM family members participate not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended CD58 loss to active immune evasion signaling, showing it represses JAK2/STAT1 via the LYN/CD22/SHP1 axis to elevate PD-L1 and IDO, and that m6A regulation destabilizes CD58 mRNA in cancer.\",\n      \"evidence\": \"Co-IP for LYN/CD22/SHP1 and HSPA4/ALKBH5, meRIP, RNA-seq/WES/scRNA-seq, and CAR-T/cytotoxicity combination assays\",\n      \"pmids\": [\"38635903\", \"38589927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic chains awaiting orthogonal confirmation\", \"How CD58 surface engagement transduces into intracellular JAK2/STAT1 suppression not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established CD58 loss as a clinically relevant mechanism of immunotherapy resistance, with deficient cells forming suboptimal synapses that cripple CAR-T and endogenous effector function.\",\n      \"evidence\": \"Genome-wide CRISPR screens with knockout validation, in vitro/in vivo CAR-T functional assays, rosetting and proximity ligation assays in primary lymphoma tissue\",\n      \"pmids\": [\"35728062\", \"32589698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative synapse defect not mechanistically linked to specific signaling deficits\", \"Strategies to restore CD58 in vivo not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple layers of CD58 regulation (PAX5/EZH2 transcription, ALKBH5 m6A, CMTM6 protein stability, soluble CD58 shedding) are integrated to set functional surface density across tissues and tumor contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking transcriptional, epigenetic, m6A, and protein-stability control\", \"Physiological role of soluble homotrimeric CD58 in modulating adhesion in vivo not established\", \"Intracellular signaling consequences of CD58 ligation in non-canonical pathways (Wnt/DKK3, JAK2/STAT1) not mechanistically connected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8, 28]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 13, 28]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 24, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD2\", \"CMTM6\", \"DKK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}