Affinage

CD40LG

CD40 ligand · UniProt P29965

Round 2 corrected
Length
261 aa
Mass
29.3 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD40LG encodes CD40 ligand (CD154/gp39), a homotrimeric type II transmembrane glycoprotein of the TNF superfamily that serves as a master orchestrator of adaptive immunity, hemostasis, and inflammation. Expressed on activated CD4+ T cells and platelets, CD40L engages CD40 on B cells to drive germinal center formation, immunoglobulin class switching via AID/UNG2-dependent somatic hypermutation, and memory B cell generation; loss-of-function mutations cause X-linked hyper-IgM syndrome (HIGM1) (PMID:7678782, PMID:7679206, PMID:7516405, PMID:24418477). CD40L also binds integrin αIIbβ3 through a KGD motif to stabilize arterial thrombi independently of CD40, and engages Mac-1 (αMβ2/CD11b) to mediate CD40-independent inflammatory leukocyte recruitment in atherosclerosis and alloimmunity (PMID:11875495, PMID:17372166, PMID:32149455). Expression is tightly controlled at multiple levels: kinetically restricted surface exposure on T cells regulated by IFN-γ and TGF-β, post-transcriptional mRNA stabilization by the PTB/PTB-T complex via a 3′UTR polypyrimidine element, epigenetic silencing in CD8+ T cells through CXXC5–SUV39H1-mediated H3K9 methylation, sex-biased overexpression in lupus through demethylation of the inactive-X allele, and proteolytic shedding from platelets that generates a biologically inert soluble form limiting inflammatory duration (PMID:8103067, PMID:12509450, PMID:26896487, PMID:17947713, PMID:11493450).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Identification of CD40LG as the TNF-family ligand for CD40 resolved a long-sought T cell signal for B cell activation, establishing that a single transmembrane protein on activated CD4+ T cells could drive B cell proliferation and, with IL-4, immunoglobulin class switching.

    Evidence cDNA cloning from activated T cells with functional reconstitution using soluble recombinant protein and CD40-Ig blocking in multiple independent labs

    PMID:1280226 PMID:1281209 PMID:1385114

    Open questions at the time
    • Oligomeric state of native protein not yet determined
    • Receptor-binding interface not mapped
    • In vivo requirement for germinal center reactions not tested
  2. 1993 High

    Demonstration that CD40LG mutations cause X-linked hyper-IgM syndrome (HIGM1) established the gene as essential for immunoglobulin isotype switching in humans and explained the B cell-intrinsic competence with a T cell-extrinsic defect.

    Evidence Mutation analysis of CD40L cDNA from HIGM1 patients, CD40-Ig binding failure of mutant proteins, rescue of B cell Ig production with wild-type recombinant CD40L

    PMID:7678782 PMID:7679206 PMID:8094231

    Open questions at the time
    • Mechanism by which CD40 signaling induces class-switch recombination machinery not defined
    • Structural basis for how mutations disrupt function unknown
  3. 1994 High

    In vivo anti-gp39 blockade proved that the CD40L–CD40 axis is required not only for class switching but specifically for germinal center formation and memory B cell generation, extending the gene's role beyond Ig secretion to the architecture of humoral immunity.

    Evidence Anti-gp39 antibody blockade in immunized mice with histological assessment of germinal centers and adoptive transfer of memory B cells

    PMID:7516405

    Open questions at the time
    • Whether CD40L signals bidirectionally back into T cells during GC reactions not addressed
    • Contribution of CD40L to affinity maturation not directly measured
  4. 1995 High

    The 2 Å crystal structure of the CD40L ectodomain revealed the expected TNF-family β-sandwich homotrimer and showed that hyper-IgM mutations cluster spatially near the CD40-binding surface, disrupting folding/stability rather than directly ablating binding contacts; complementary mutagenesis mapped the binding interface to residues from two adjacent monomers.

    Evidence X-ray crystallography at 2 Å resolution; site-directed mutagenesis of gp39 and CD40 guided by TNFβ/TNFR structural modeling

    PMID:7543281 PMID:8589998

    Open questions at the time
    • No co-crystal structure of the CD40L–CD40 complex available
    • Structural basis for alternative receptor (integrin) binding unknown
  5. 1995 High

    Discovery that gp39–CD40 interactions are required for thymic negative selection of endogenous superantigens expanded CD40L's role beyond peripheral B cell help to central T cell tolerance, mediated partly through regulation of B7-2 expression on thymic APCs.

    Evidence Anti-gp39 blockade and gp39-deficient mice with TCR Vβ repertoire analysis and B7-2 immunohistochemistry

    PMID:7595208

    Open questions at the time
    • Whether this applies to peptide/MHC-driven negative selection not established
    • Downstream signaling in thymic APCs not dissected
  6. 1998 High

    The finding that platelets carry preformed CD40L that is rapidly surface-exposed upon activation fundamentally recast CD40L as a bridge between hemostasis and inflammation, showing it activates endothelial cells to express adhesion molecules and secrete chemokines equivalently to TNF-α.

    Evidence Flow cytometry and immunofluorescence of thrombi in vivo; endothelial activation assays with ELISA for chemokines and adhesion molecules

    PMID:9468137

    Open questions at the time
    • Protease responsible for CD40L shedding from platelets not identified
    • Relative contribution of platelet vs. T cell CD40L to vascular inflammation in vivo not quantified
  7. 2001 High

    Characterization of proteolytic shedding of platelet CD40L to a biologically inert 18-kDa soluble form revealed a self-limiting mechanism that temporally restricts inflammation at thrombus sites, and subcellular fractionation placed CD40L in the platelet cytoplasm (not α-granule membrane), with surface mobilization dependent on Ca²⁺/PKC signaling.

    Evidence Flow cytometry kinetics, immunoblot, endothelial activation comparison of membrane vs. soluble forms, subcellular fractionation, pharmacological inhibitor panel

    PMID:11297035 PMID:11493450

    Open questions at the time
    • Identity of the shedding protease not determined
    • Whether sCD40L retains any signaling capacity on non-endothelial targets not excluded
  8. 2002 High

    Demonstration that CD40L stabilizes arterial thrombi by directly binding integrin αIIbβ3 via a KGD motif — independent of CD40 — established CD40L as a bivalent ligand acting through distinct receptors in immunity vs. thrombosis.

    Evidence CD40L-KO and CD40-KO mice in ferric chloride thrombosis model, KGD-mutant reconstitution, purified αIIbβ3 binding assay, platelet spreading and aggregation under high shear

    PMID:11875495

    Open questions at the time
    • Structural basis of KGD-αIIbβ3 interaction not resolved
    • Whether CD40L competes with fibrinogen for αIIbβ3 binding not clarified
  9. 2003 High

    Identification of PTB and PTB-T as opposing regulators of CD154 mRNA stability via a 3′UTR polypyrimidine element revealed a post-transcriptional checkpoint governing the amount and duration of CD40L surface expression on T cells.

    Evidence RNA-protein pulldown with protein sequencing, cotransfection reporter assays, mRNA decay analysis

    PMID:12509450

    Open questions at the time
    • Upstream signals that shift PTB vs. PTB-T cytoplasmic ratio not identified
    • Whether this mechanism operates in platelets or other CD40L-expressing cells unknown
  10. 2007 High

    Two discoveries broadened CD40L's biology beyond CD40: (1) CD40L engages Mac-1 (αMβ2) as an alternative inflammatory receptor — explaining why CD40L-KO but not CD40-KO mice show reduced atherosclerosis — and (2) demethylation of CD40LG on the inactive X chromosome in women with lupus causes sex-biased overexpression, linking epigenetics to autoimmunity.

    Evidence Radioactive binding/IP of CD40L-Mac-1, CD40-KO vs. CD40L-KO atherogenesis models, Mac-1 peptide blockade; bisulfite sequencing of CD40LG locus, 5-azacytidine treatment with sex-stratified flow cytometry

    PMID:17372166 PMID:17947713

    Open questions at the time
    • Mac-1 binding site on CD40L not structurally mapped
    • Whether inactive-X demethylation is cause or consequence of lupus not resolved
    • Contribution of Mac-1 vs. αIIbβ3 pathways to different vascular beds unclear
  11. 2010 High

    A CD40/TAK1/NF-κB signaling cascade was delineated in platelets, showing that sCD40L primes platelets for aggregation at subthreshold agonist concentrations; in parallel, platelet-derived CD40L was shown to drive sepsis-induced lung injury indirectly via MIP-2/CXCR2 and to potentiate IFN-α from plasmacytoid DCs in lupus.

    Evidence CD40-KO platelets with TAK1/NF-κB inhibitors and aggregation assays; CLP sepsis model in CD40L-KO mice with CXCR2 inhibition; SLE platelet-pDC co-culture with blocking antibodies

    PMID:19806052 PMID:20811042 PMID:30571597

    Open questions at the time
    • Downstream NF-κB targets in platelets not catalogued
    • Whether TAK1/NF-κB pathway also mediates αIIbβ3-dependent thrombus stability not tested
  12. 2014 High

    Molecular analysis of HIGM1 patient B cells revealed that CD40L deficiency impairs AID and UNG2 enzymatic activity and skews somatic hypermutation, establishing that CD40 signaling transcriptionally controls DNA repair genes required for antibody diversification and selection against autoreactivity.

    Evidence AID/UNG2 activity assays and IgA/IgG heavy chain transcript sequencing in CD40L-deficient patients vs. controls

    PMID:24418477

    Open questions at the time
    • Direct transcriptional targets of CD40 signaling in SHM-related DNA repair not enumerated
    • Whether residual SHM in HIGM1 reflects CD40L-independent AID induction not resolved
  13. 2016 High

    Epigenetic silencing of CD40LG in CD8+ T cells was traced to a CXXC5–SUV39H1 complex that deposits H3K9 methylation at the Cd40lg promoter; ThPOK de-represses CD40LG by inhibiting CXXC5, revealing how lineage-specific transcription factors enforce the CD4-restricted expression pattern.

    Evidence Retroviral ThPOK transduction into CD8+ T cells, ChIP for histone marks, CXXC5-SUV39H1 co-immunoprecipitation

    PMID:26896487

    Open questions at the time
    • Whether CXXC5 recruits additional chromatin modifiers beyond SUV39H1 not tested
    • How platelet-lineage cells bypass this epigenetic silencing mechanism is unexplained
  14. 2020 High

    Functional separation of CD40L's two receptor interfaces in transplant models — using CD40-KO hosts and CD154–CD11b-specific peptide antagonists — confirmed that CD40L–Mac-1 drives a non-redundant inflammatory pathway in alloimmunity that is therapeutically targetable independently of CD40.

    Evidence Fully allogeneic murine transplant in CD40-/- hosts, CD154-CD11b interface-selective peptide plus anti-CD40 combination, graft-infiltrating cell analysis

    PMID:32149455

    Open questions at the time
    • Structural basis of selective peptide blockade of CD154-CD11b not resolved
    • Whether dual receptor blockade achieves tolerance vs. immunosuppression not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease(s) responsible for CD40L shedding from platelets, the co-crystal structure of CD40L bound to each of its three receptors (CD40, αIIbβ3, Mac-1), the mechanism by which platelet-lineage cells escape CD8-type epigenetic silencing of CD40LG, and whether targeting individual receptor interfaces can selectively modulate immunity vs. thrombosis vs. inflammation.
  • Shedding protease identity unknown
  • No co-crystal structures with any receptor
  • Platelet-lineage epigenetic regulation not studied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005576 extracellular region 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-1643685 Disease 4 R-HSA-109582 Hemostasis 3 R-HSA-162582 Signal Transduction 3
Partners
CD40CXXC5ITGA2BITGAMITGB2ITGB3PTBP1SUV39H1
Complex memberships
CD40L homotrimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 CD40LG (gp39/TRAP/CD40L) encodes a 261 amino acid type II transmembrane protein homologous to TNF, expressed on activated T cells, that functions as the ligand for CD40 on B cells; a soluble recombinant form retains B cell co-stimulatory activity, driving B cell proliferation in concert with anti-CD20 or PMA, and this activity is blocked by soluble CD40. cDNA cloning, COS cell transfection, soluble fusion protein blocking assay, B cell proliferation assay The EMBO journal High 1385114
1992 Human CD40L (hCD40-L) is a 261 amino acid type II membrane protein with 78% amino acid identity to murine CD40L, predominantly expressed on CD4+ T cells; recombinant hCD40L induces B cell proliferation and, with IL-4, drives IgE secretion from purified B cells. cDNA cloning by cross-hybridization, Northern blot, FACS, B cell proliferation/IgE secretion assay The Journal of experimental medicine High 1281209
1992 TRAP (TNF-related activation protein), the human homolog later named CD40LG, is a type II transmembrane protein encoded on the X chromosome (Xq26.3–q27.1), T-cell-specifically expressed with peak mRNA at 8 h post-stimulation, and identified as the CD40 ligand by binding to a soluble CD40 construct. cDNA cloning from T cell activation library, Northern blot, chromosomal mapping, soluble CD40 binding assay European journal of immunology High 1280226
1993 Mutations in the extracellular domain of gp39 (CD40LG) are the molecular basis of X-linked hyper-IgM syndrome (HIM); HIM T cells fail to bind CD40-Ig despite normal gp39 mRNA levels, and recombinant mutant gp39 proteins cannot bind CD40 or drive B cell proliferation. The gene maps to Xq26. Mutation analysis, CD40-Ig binding assay, recombinant protein functional assay, chromosomal mapping Cell High 7678782
1993 Point mutations in CD40LG result in defective or absent CD40L protein on T cells from HIGM1 patients, preventing CD40 ligation and thereby causing the immunoglobulin isotype switch defect; B cells from affected patients respond normally to wild-type CD40L. Mutation analysis of CD40L cDNA, functional B cell assays with recombinant CD40L Nature High 7679206 7679801 8094231
1993 CD40L expression on activated CD4+ T cells is kinetically regulated: detectable at 4 h, peak at 6–8 h, and declining by 24–48 h after anti-CD3 stimulation; IFN-γ inhibits gp39 expression on Th1, Th2, and CD4+ T cells, while TGF-β inhibits expression on Th2 clones only; CD8+ T cells activated by anti-CD3 do not express gp39 but PMA/ionomycin-activated CD8+ T cells do. Flow cytometry, cytokine treatment of T cell clones and splenic CD4+ T cells, anti-CD3 stimulation kinetics Journal of immunology High 8103067
1993 IL-13, like IL-4, synergizes with CD40L to induce B cell proliferation and immunoglobulin class switching (including IgE), through a mechanism independent of IL-4 (not blocked by anti-IL-4); B cell differentiation requires specific CD40 engagement as shown by inhibition with soluble CD40. COS-7/hCD40L co-culture with purified B cells, Ig secretion assay, cytokine blocking with anti-IL-4 antibody, soluble CD40 inhibition International immunology High 7688562
1994 In vivo blockade of gp39-CD40 interactions with anti-gp39 antibody completely inhibits germinal center formation and prevents generation of antigen-specific memory B cells following immunization, establishing that gp39-CD40 interactions are required for both germinal center development and B cell memory. In vivo antibody blockade, immunohistochemical staining for germinal centers, adoptive transfer of memory B cells The Journal of experimental medicine High 7516405
1995 Activated B cells express a CD40 ligand identical in sequence to T cell-expressed CD40LG; B cell-expressed CD40L drives homotypic B cell aggregation and enhances Ig production in a CD40-dependent manner, and B cell lines expressing CD40L can induce Ig production from resting normal B cells. CD40.Ig fusion protein binding, surface 125I-labeling immunoprecipitation, RT-PCR sequencing, Ig production assay, CD40.Ig inhibition Journal of immunology High 7537298
1995 Crystal structure of the extracellular fragment of human CD40L determined at 2 Å resolution reveals a homotrimer with a TNF-family β-sandwich fold; hyper-IgM syndrome mutations are dispersed in primary sequence but cluster spatially near a surface loop adjacent to the predicted CD40-binding site, suggesting they primarily disrupt folding/stability rather than directly ablating the binding interface. X-ray crystallography at 2 Å resolution Structure High 8589998
1995 Site-directed mutagenesis guided by molecular models of the gp39/CD40 complex (based on TNF-β/TNFR crystal structure template) identified key gp39 residues (K143, Y145, Y146, R203, Q220) and CD40 residues (E74, Y82, D84, N86, E117) required for the interaction; the gp39-CD40 binding interface involves at least two clusters of residues and contributions from two adjacent gp39 monomers. Molecular modeling using TNF-β/TNFR complex as template, site-directed mutagenesis, binding assay Biochemistry High 7543281
1995 gp39-CD40 interactions are required for negative selection (thymic deletion) of T cells bearing endogenously expressed antigens/superantigens but not for deletion by exogenously administered high-dose antigen; gp39 is expressed on antigen-stimulated thymocytes and gp39 deficiency reduces thymic B7-2 expression, suggesting gp39 influences negative selection by regulating costimulatory molecule expression. In vivo anti-gp39 antibody blockade, gp39-deficient mice, TCR Vβ repertoire analysis, AND TCR transgenic mice, B7-2 immunohistochemistry The Journal of experimental medicine High 7595208
1997 Transgenic overexpression of gp39 in the thymus causes dose-dependent thymocyte depletion (>500-fold), loss of cortical epithelium, and expansion of CD40+ medullary cells; peripheral tissues develop chronic inflammatory disease and lethal inflammatory bowel disease in high-copy animals; these defects are partly attributed to saturation of a mechanism that sequesters gp39 inside non-activated cells, preventing inappropriate gp39-CD40 interactions. Transgenic mouse generation, bone marrow transplantation, histopathology, dose-dependent transgene analysis International immunology High 9263008
1998 Platelets express preformed CD40L (CD154) that rapidly appears on the platelet surface within seconds of activation in vitro and during thrombus formation in vivo; platelet-surface CD40L activates endothelial cells to secrete chemokines and express adhesion molecules (E-selectin, VCAM-1, ICAM-1), thereby initiating inflammatory recruitment of leukocytes—effects equivalent to TNF-α and IL-1. Flow cytometry, immunofluorescence of thrombi in vivo, endothelial cell activation assay, ELISA for chemokines/adhesion molecules Nature High 9468137
2001 Platelet CD40L expression is temporally self-limited: CD40 is constitutively expressed on platelets, and binding of CD40L to platelet CD40 in the aggregate leads to proteolytic cleavage and release of an 18-kDa soluble form of CD40L within minutes to hours; soluble CD40L (sCD40L) cannot activate endothelial cells, providing a regulatory mechanism to restrict the duration of inflammation at the thrombus site. Flow cytometry, immunoblot, endothelial activation assay comparing membrane vs. soluble CD40L forms, kinetic analysis Blood High 11493450
2001 Platelet CD40L subcellular localization is cytoplasmic (not granule-membrane like CD62P/CD63); surface expression is induced by multiple platelet activators and depends on internal Ca2+ stores and protein kinase C but not ERK/p38 MAP kinases or tyrosine kinases; ADP-induced CD40L expression is abolished by clopidogrel (P2Y12 antagonism) but not aspirin. Quantitative flow cytometry, immunofluorescence microscopy, subcellular fractionation Western blotting, pharmacological inhibitors, MEG-01 cell line studies Platelets High 11297035
2002 CD40L stabilizes arterial thrombi via direct binding to integrin αIIbβ3 (not through CD40): CD40L-deficient mice have impaired thrombus stability and delayed arterial occlusion; infusion of recombinant soluble CD40L restores normal thrombosis but a KGD-motif mutant lacking the integrin-recognition sequence does not; recombinant CD40L binds purified αIIbβ3 specifically, induces platelet spreading, and promotes high-shear platelet aggregation; CD40-deficient mice show normal thrombogenesis. In vivo ferric chloride carotid artery thrombosis model, CD40L-KO and CD40-KO mice, recombinant protein infusion, KGD motif mutagenesis, αIIbβ3 binding assay, platelet spreading/aggregation assay Nature medicine High 11875495
2002 GPIIb/IIIa (αIIbβ3) engagement on platelets upregulates CD40L surface exposure; platelet-endothelium adhesion via αIIbβ3 triggers CD40L-dependent proteolytic activity in endothelial cells (upregulation of uPA receptor, MT1-MMP, secretion of uPA, tPA, MMP-1, and activation of MMP-2/MMP-9), effects blocked by anti-CD40L antibody TRAP1 or GPIIb/IIIa antagonists. Platelet-endothelial cell co-culture with transwell controls, reverse transcriptase-PCR, flow cytometry, ELISA, gelatin zymography, blocking antibodies and integrin antagonists Circulation High 12379582
2003 CD40LG mRNA stability and expression are regulated post-transcriptionally through a novel cis-acting instability element in the polypyrimidine-rich region of the CD154 3'UTR; the two major 3'UTR-binding proteins are polypyrimidine tract-binding protein (PTB) and a novel alternatively spliced isoform PTB-T; PTB-T decreases CD154 3'UTR-dependent reporter expression while PTB tends to increase it, indicating that the relative cytoplasmic levels of PTB vs. PTB-T regulate CD154 mRNA accumulation. RNA-protein pulldown/purification, protein sequencing, cotransfection reporter assays, tetracycline-responsive reporter mRNA decay assay Molecular and cellular biology High 12509450
2007 CD40L interacts with Mac-1 (integrin αMβ2/CD11b) independently of CD40, mediating inflammatory cell adhesion, migration, and myeloperoxidase release; CD40-deficient mice do not show reduced atherosclerotic lesion area whereas CD40L-deficient mice have impaired peritoneal inflammatory cell recruitment; Mac-1 inhibition in LDL receptor-deficient mice attenuates atherosclerosis and macrophage accumulation. Flow cytometry, radioactive binding assays, immunoprecipitation, CD40-KO and CD40L-KO mouse models, thioglycolate peritonitis model, atherogenic diet experiments with Mac-1 inhibition Circulation High 17372166
2007 Demethylation of CpG sequences at CD40LG on the inactive X chromosome in CD4+ T cells from women with lupus leads to overexpression of CD40L specifically in women; bisulfite sequencing shows women have one methylated and one unmethylated CD40LG allele, while 5-azacytidine doubles CD40LG expression in women but not men; women (not men) with lupus show CD40LG demethylation and overexpression. Bisulfite sequencing, 5-azacytidine treatment, flow cytometry for CD40L surface expression, comparison of lupus patients vs. controls Journal of immunology High 17947713
2009 CD40L post-transcriptional regulation in CD4+ T cells is mediated by PTB-complex-dependent stabilization of the CD154 transcript upon activation; the CD154 mRNA is subject to activation-induced stabilization through a polypyrimidine tract-binding protein complex, constituting a key temporal control point for precise surface CD154 levels during antigen stimulation. mRNA decay analysis, PTB-complex binding studies, reporter assays (as reviewed and mechanistically supported by PMID:12509450) RNA biology Medium 19395873
2010 CD40L (CD154) activates platelet NF-κB via CD40/TAK1 signaling: sCD40L dose-dependently induces platelet NF-κB activation in a CD40-dependent manner (absent in CD40-/- mouse platelets and inhibited by CD40 blockade, but not affected by αIIbβ3 or α5β1 blockade); TAK1 acts upstream of NF-κB in this pathway; sCD40L/CD40/TAK1/NF-κB signaling primes platelets and potentiates aggregation in response to subthreshold thrombin, an effect blocked by CD40, TAK1, or NF-κB inhibitors. NF-κB activation assay in CD40-/- and wild-type mouse platelets, receptor-specific blocking antibodies, pharmacological inhibition of TAK1 and NF-κB, platelet aggregation assay Journal of the American Heart Association High 30571597
2010 CD154 (CD40L) plays a protective role in hepatic steatosis: CD154-KO mice on an olive oil-rich diet develop hepatic steatosis associated with reduced apoB100 expression and decreased VLDL secretion; this correlates with impaired UPR (reduced XBP1 mRNA splicing and reduced eIF2α phosphorylation); soluble CD154 treatment of hepatocytes increases XBP1 splicing in OA or tunicamycin-stressed cells and reduces OA-induced inhibition of apoB100 secretion in an XBP1- and IRE1-dependent manner. CD154-KO mouse dietary model, VLDL secretion assay, apoB100 immunoblot, XBP1 mRNA splicing, eIF2α phosphorylation, XBP1 siRNA knockdown, dominant-negative IRE1 construct, primary hepatocyte cultures Hepatology High 21064031
2010 Platelet-derived CD40L drives sepsis-induced neutrophil Mac-1 upregulation and lung edema indirectly via MIP-2 (CXCL2) formation and CXCR2 signaling: platelet depletion reduces CLP-induced sCD40L by 90%; CD40L-deficient mice show abolished Mac-1 upregulation on neutrophils and reduced lung edema/myeloperoxidase activity; CD40L does not directly increase Mac-1 on neutrophils in vitro; CLP-induced MIP-2 levels are reduced in CD40L-deficient mice; CXCR2 inhibition decreases Mac-1 expression. CLP model in CD40L-KO and wild-type mice, platelet depletion with anti-GP1bα, Mac-1 flow cytometry, bronchoalveolar lavage, CXCR2 inhibition, in vitro neutrophil stimulation Annals of surgery High 19806052
2010 Platelet CD154 potentiates IFN-α secretion by plasmacytoid dendritic cells (pDCs) in SLE through direct CD154-CD40 interaction: SLE platelets are activated by immune complexes via FcγRIIA (CD32), form aggregates with monocytes and pDCs, and enhance immune complex-stimulated IFN-α production; this IFN-α enhancement requires CD154-CD40 interaction. Patient sample analysis, flow cytometry, platelet-pDC co-culture, IFN-α ELISA, CD154-CD40 blocking antibodies, FcγRIIA blocking, lupus-prone mouse platelet depletion/transfusion experiments with clopidogrel treatment Science translational medicine High 20811042
2014 CD40L deficiency leads to impaired antibody selection and altered somatic hypermutation: CD40L-deficient patients have reduced activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2) activity, decreased usage of IgM-distal IgG2 and IgA2 subclasses, lower mutation load in class-switched transcripts, impaired selection of mutations for antigen binding, and reduced selection against autoreactive immunoglobulins; CD40 signaling transcriptionally regulates DNA repair genes involved in somatic hypermutation. Flow cytometry of B cell subsets, molecular analysis of IgA/IgG heavy chain transcripts, AID/UNG2 activity assays, B cell activation studies in CD40L-deficient patients vs. controls The Journal of allergy and clinical immunology High 24418477
2016 CD40LG expression in CD8+ cytotoxic T cells is epigenetically repressed by CpG methylation, H3K9me, H3K27me, and H4K20me at the promoter; ThPOK (Zbtb7b) induces moderate CD40L expression in CD8+ T cells by reducing H3K9me and H3K27me; ThPOK directly inhibits CXXC5 expression, and CXXC5 promotes H3K9 methylation at the Cd40lg promoter by interacting with the methyltransferase SUV39H1. Retroviral Thpok transduction into CD8+ T cells, ChIP for histone modifications, CXXC5 transgene expression, co-immunoprecipitation of CXXC5 with SUV39H1, reporter assays Journal of leukocyte biology High 26896487
2012 Periodontopathogens (A. actinomycetemcomitans and P. gingivalis) directly induce surface CD40L expression on human platelets via TLR2 and TLR4 (but not FcγRII), in a plasma factor (CD14)-dependent process requiring PI3K and PLC signaling; this mechanism links periodontal infection to elevated sCD40L and increased cardiovascular risk. Flow cytometry of platelet CD40L after pathogen exposure, TLR blocking antibodies, PI3K/PLC inhibitors, FcγRII blocking, patient plasma sCD40L measurements Thrombosis research High 22608210
2020 CD154 (CD40L) binds CD11b (Mac-1/αMβ2 integrin) as a novel alternative receptor during alloimmunity: anti-CD154 prolongs graft survival in CD40-/- hosts; a specific peptide antagonist blocking CD154-CD11b interaction (without affecting CD154-CD40) enhances anti-CD40 efficacy for graft survival and reduces graft-infiltrating CD8+ T cells and innate immune cells. Fully allogeneic murine transplant model, CD40-/- hosts, CD154-specific peptide antagonist blocking only the CD154-CD11b interface, graft survival analysis, flow cytometry of graft-infiltrating cells American journal of transplantation High 32149455
2014 Platelet CD154 promotes allergic asthma by inhibiting Foxp3+ regulatory T cell induction: OVA-activated platelets upregulate CD154; platelet transfer worsens asthma (leukocyte infiltration, IgE, Th2 responses) while platelet depletion attenuates it; Cd154-deficient platelets fail to promote asthma; platelets inhibit Foxp3+ Treg induction in vivo and in vitro at least partly through CD154. OVA asthma mouse model, platelet transfer and depletion experiments, Cd154-KO platelets, Foxp3+ Treg quantification by flow cytometry Cellular & molecular immunology High 25418472
2009 Platelet CD40L induces activation of astrocytes and microglia via CD40 signaling and NF-κB/MAPK inflammatory pathways: ADP-activated platelets deposit in the brain in hypertension and release sCD40L; sCD40L activates astrocytes and microglia in vitro and in vivo; CD40 disruption or clopidogrel prevents glial activation and provides neuroprotection. Rat hypertension model, ADP-activated platelet injection into normotensive rats, in vitro glial cell CD40L stimulation, NF-κB/MAPK Western blotting, clopidogrel treatment, CD40 signaling blockade Brain, behavior, and immunity Medium 27658543

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1646 9468137
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 CD40 and CD154 in cell-mediated immunity. Annual review of immunology 1165 9597126
2000 CD40-CD40 ligand. Journal of leukocyte biology 1128 10647992
1993 The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 748 7678782
1993 CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science (New York, N.Y.) 726 7679801
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1993 Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 652 7679206
1993 CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature 632 8094231
2001 The CD40/CD154 receptor/ligand dyad. Cellular and molecular life sciences : CMLS 606 11229815
2002 CD40L stabilizes arterial thrombi by a beta3 integrin--dependent mechanism. Nature medicine 600 11875495
1992 The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. The EMBO journal 543 1385114
2004 CD40/CD154 interactions at the interface of tolerance and immunity. Annual review of immunology 521 15032580
1996 Immune regulation by CD40 and its ligand GP39. Annual review of immunology 504 8717526
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1996 Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. The Journal of biological chemistry 418 8910514
1992 Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. The Journal of experimental medicine 416 1281209
1994 gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. The Journal of experimental medicine 367 7516405
2001 The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 356 11493450
2007 Demethylation of CD40LG on the inactive X in T cells from women with lupus. Journal of immunology (Baltimore, Md. : 1950) 348 17947713
2009 The role of CD40 and CD154/CD40L in dendritic cells. Seminars in immunology 344 19524453
1993 The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 333 8103067
1993 In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. The Journal of experimental medicine 312 7693850
1995 Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. Journal of immunology (Baltimore, Md. : 1950) 296 7529804
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