Affinage

Showing CD40LG — CD40L is a alias.

CD40LG

CD40 ligand · UniProt P29965

Length
261 aa
Mass
29.3 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD40LG encodes CD154 (CD40L), a TNF-superfamily ligand whose central function is to provide CD40-dependent T-cell help that licenses B-cell isotype switching, germinal-center maturation, and inflammatory cell–cell signaling (PMID:7915248, PMID:10510350). The crystal structure of the CD40–CD154 complex shows CD40 binding within a crevice between two CD154 subunits governed by charge complementarity, and demonstrates that ligand-induced di/trimerization is necessary but not sufficient for full receptor activation, since the Ser132 loop modulates p38- and ERK-dependent signaling without affecting JNK (PMID:21285457). Beyond CD40, CD154 engages integrin α5β1 and αvβ3 at the trimeric interface and CD11b (Mac-1), and these alternative receptors contribute independently to NF-κB activation, B-cell activation, and alloimmunity (PMID:31331973, PMID:32149455). Loss-of-function mutations in CD40LG cause X-linked hyper-IgM syndrome (HIGM1) by abrogating CD40 engagement and isotype switching; many HIGM1 mutations map to the CD40-binding interface or to the integrin-binding site (PMID:21285457, PMID:31331973, PMID:7915248), and CD40L deficiency additionally impairs AID/UNG2-dependent somatic hypermutation and selection against autoreactive antibodies (PMID:24418477). CD154 expression is tightly controlled: transcriptionally through glucocorticoid-receptor and IL-12 signaling (PMID:11160161, PMID:9570530), epigenetically by X-chromosome DNA methylation and by ThPOK–CXXC5–SUV39H1-driven histone H3K9 methylation that represses the gene in CD8+ T cells (PMID:17947713, PMID:26896487), and post-transcriptionally through a polypyrimidine-rich 3'UTR instability element bound by PTB and the PTB-T isoform that set CD154 mRNA stability and the temporal kinetics of surface expression (PMID:12509450, PMID:10201926). A second major source of CD154 is the platelet, where it is stored in a distinct compartment and translocated to the surface and released upon activation via Ca2+/PKC- and P2Y12-dependent mechanisms (PMID:11297035, PMID:36055226); platelet-derived CD154 is sufficient to drive cardiac allograft rejection, sepsis-associated neutrophil recruitment via MIP-2/CXCR2, glial neuroinflammation, autoreactive B-cell activation, and CD8+ anti-tumor T-cell responses (PMID:15191945, PMID:16498500, PMID:19806052, PMID:36055226, PMID:27658543). Through CD40 on endothelium, hepatocytes, podocytes, and dendritic cells, CD154 elicits chemokine production, FasL-mediated apoptosis, MMP-9 secretion, and IL-12p70-dependent T-cell priming, placing it at the center of vascular inflammation, atherosclerotic plaque destabilization, and the tolerance-versus-immunity decision (PMID:14976003, PMID:10648122, PMID:10546000, PMID:16025512, PMID:27070919, PMID:19609245, PMID:19841180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Establishing that defective CD40L causes X-linked hyper-IgM syndrome answered why some immunodeficiencies present with failed isotype switching despite intact IgM, defining CD40L as the essential T-cell help signal for class switching.

    Evidence Genetic mapping, cDNA sequencing, mutation analysis, and B–T cell interaction assays in HIGM1 patients

    PMID:7915248

    Open questions at the time
    • Did not resolve the structural basis of how individual mutations disrupt CD40 binding
    • Did not address non-CD40 receptors or platelet sources of CD40L
  2. 1998 Medium

    Identifying IL-12 (synergizing with IL-2 and B7/CD28) as an inducer of T-cell CD40L showed that cytokine cues feed into CD40L-mediated humoral help, explaining how innate signals shape antibody responses.

    Evidence Anti-CD3 ± IL-12 T-cell stimulation, RT-PCR, flow cytometry, B-cell proliferation/IgG assays with anti-CD40L blockade

    PMID:9570530

    Open questions at the time
    • Transcription factors linking IL-12 to the CD40LG promoter not identified
    • Did not separate transcriptional from post-transcriptional contributions
  3. 1999 High

    Demonstrating that CD154–CD40 ligation drives endothelial chemokine output and that CD40L signaling promotes atherosclerotic plaque destabilization positioned CD40L as a central effector of vascular inflammation, not solely a lymphocyte signal.

    Evidence HUVEC co-culture chemotaxis assays with anti-CD154 blockade; CD154 knockout in ApoE-/- mice with plaque morphometry

    PMID:10546000 PMID:10648122

    Open questions at the time
    • Cellular source of CD154 driving plaque pathology not fully resolved
    • Downstream receptor on responding vascular cells beyond CD40 not examined
  4. 1999 Medium

    Showing germinal-center B cells express CD154 and that CD154 itself transmits costimulatory signals revealed bidirectional CD40–CD154 signaling and a B-cell-intrinsic role in memory differentiation.

    Evidence Ex vivo tonsillar B-cell analysis, anti-CD154 blockade, CD154-Sepharose bead signaling assays

    PMID:10510350

    Open questions at the time
    • Intracellular signaling components downstream of CD154 reverse signaling not mapped
    • Single-lab bead-based readout
  5. 1999 Medium

    Measuring CD154 mRNA decay kinetics during T-cell activation established that post-transcriptional stability control, distinct from TNF-α, shapes the temporal surface expression of CD40L.

    Evidence mRNA decay assays in primary CD4+ T cells under multiple stimulation conditions

    PMID:10201926

    Open questions at the time
    • Did not identify the cis-element or trans-acting factors
    • Mechanism of activation-induced stabilization unresolved
  6. 2001 High

    Identifying glucocorticoid-receptor-driven transcriptional induction of CD40L and localizing CD40L to a distinct platelet storage compartment answered how CD40L is regulated at the transcriptional level and revealed platelets as a second, activation-released source.

    Evidence CD40L-deficient patient cells with RU-486/actinomycin D and CD40-Ig blockade; platelet subcellular fractionation, flow cytometry, and pharmacological dissection

    PMID:11160161 PMID:11297035

    Open questions at the time
    • Direct GR binding site on CD40LG not mapped
    • Identity of the platelet storage compartment not molecularly defined
  7. 2003 High

    Resolving the 3'UTR instability element and its PTB/PTB-T binding proteins provided the molecular basis for post-transcriptional control of CD154, explaining how relative PTB isoform levels tune mRNA accumulation.

    Evidence RNA pulldown/sequencing, luciferase and tetracycline-decay reporters, PTB/PTB-T cotransfection

    PMID:12509450

    Open questions at the time
    • How activation signals shift PTB vs PTB-T levels not established
    • In vivo relevance to physiological CD40L kinetics not directly tested
  8. 2004 Medium

    Demonstrating platelet-derived CD154 activates autoreactive B cells and an endothelial-monocyte CD154 feedback loop extended CD40L function into autoimmunity and inflammatory amplification beyond classical T–B help.

    Evidence ITP patient platelet–B cell co-cultures with antibody production assays; endothelial-monocyte transmigration assays with anti-CD154 blockade

    PMID:14976003 PMID:15191945

    Open questions at the time
    • Relative in vivo contribution of platelet vs T-cell CD154 not quantified here
    • Signaling pathways inducing endothelial CD154 not detailed
  9. 2005 Medium

    Showing CD40 acts as a primary platelet signaling receptor for CD40L and that the CD40–CD40L dyad supports hemostasis, plus a CD154-driven hepatocyte apoptosis pathway, broadened the receptor's roles into thrombosis and tissue injury.

    Evidence CD40/CD40L-KO mice bleeding/closure assays with recombinant trimeric sCD40L; con A hepatitis KO model with in vitro TNF-α/CD40/FasL apoptosis assays

    PMID:15968400 PMID:16025512

    Open questions at the time
    • Platelet intracellular signaling downstream of CD40 not defined
    • Contribution of FcγRII vs CD40 routes not fully separated
  10. 2006 High

    Reconstituting cardiac allograft rejection with platelet- or recombinant-CD154 in CD154-KO hosts proved platelet CD154 is sufficient, independent of T-cell CD154, to drive alloimmune rejection.

    Evidence Murine cardiac allograft model with CD154-KO recipients, platelet transfusion, recombinant trimer infusion, and 5c8 mAb blockade

    PMID:16498500

    Open questions at the time
    • Receptor(s) on graft and immune cells mediating rejection not pinpointed
    • Requirement of platelet activation for trimer sufficiency mechanistically unexplained
  11. 2007 Medium

    Defining Cys238-dependent disulfide-linked CD40 homodimers in detergent-resistant membranes as required for downstream cytokine output clarified the receptor-side biochemical mechanism enabling bidirectional CD40–CD154 signaling.

    Evidence Cys238 mutagenesis, co-IP, membrane fractionation, cytokine ELISAs, superantigen T-cell co-cultures

    PMID:17504764

    Open questions at the time
    • Whether CD154 trimerization directly templates the disulfide dimer not shown
    • Single-lab biochemical model
  12. 2009 High

    Placing platelet CD40L upstream of MIP-2/CXCR2-driven neutrophil recruitment, glial neuroinflammation, and IL-12-dependent DC priming established the effector pathways through which CD40L converts platelet/T-cell activation into innate inflammation and the tolerance-versus-immunity decision.

    Evidence CD40L-KO sepsis (CLP) model with platelet depletion and CXCR2 inhibition; hypertension model with clopidogrel/anti-CD40 blockade; CD154-/- apoptotic T-cell and IL-12p40-/- adoptive transfer; adenoviral CD40L DC IL-12p70 assays

    PMID:19609245 PMID:19806052 PMID:19841180 PMID:27658543

    Open questions at the time
    • Direct vs indirect actions on each responding cell type not fully separated in all models
    • Receptor identity on glia and DCs assumed to be CD40
  13. 2011 High

    The CD40–CD154 crystal structure with functional mutagenesis answered how the ligand engages CD40 and why oligomerization alone is insufficient, mapping HIGM1 mutations to the interface and dissociating p38/ERK from JNK signaling outputs.

    Evidence X-ray crystallography at 3.5 Å with site-directed mutagenesis and signaling assays

    PMID:21285457

    Open questions at the time
    • Structural basis for differential MAPK branch activation not resolved
    • Integrin-binding interface not visualized in this structure
  14. 2014 Medium

    Showing CD40L deficiency impairs AID/UNG2 activity, somatic hypermutation quality, and selection against autoreactive antibodies refined the HIGM1 phenotype beyond simple isotype switching to the molecular machinery of affinity maturation.

    Evidence B-cell subset flow cytometry and Ig transcript/SHM analysis in CD40L-deficient patients vs controls

    PMID:24418477

    Open questions at the time
    • Transcriptional link between CD40 signaling and DNA-repair gene regulation not mechanistically detailed
    • Single patient-cohort study
  15. 2016 Medium

    Defining a ThPOK–CXXC5–SUV39H1 axis that imposes H3K9 methylation at the Cd40lg promoter explained how CD40L is epigenetically silenced in CD8+ T cells, complementing X-chromosome methylation findings in autoimmunity.

    Evidence ChIP for histone marks, retroviral ThPOK transduction, CXXC5 transgenes, SUV39H1 co-IP; bisulfite sequencing with 5-azacytidine in human T cells

    PMID:17947713 PMID:26896487

    Open questions at the time
    • How these epigenetic states are dynamically reset upon activation unclear
    • Single-lab studies for each mechanism
  16. 2019 Medium

    Identifying integrin α5β1/αvβ3 binding at the trimeric interface, distinct from the CD40 site, revealed CD40L receptors beyond CD40 and explained an additional class of HIGM1 mutations and the antagonist behavior of integrin-binding-defective mutants.

    Evidence Docking, integrin-mutant binding assays, NF-κB reporters, B-cell activation assays

    PMID:31331973

    Open questions at the time
    • In vivo contribution of integrin binding to CD40L function not established
    • No structure of the CD40L-integrin complex
  17. 2020 Medium

    Demonstrating CD11b (Mac-1) as a CD154 receptor whose blockade synergizes with anti-CD40 to control alloimmunity showed CD40 alone does not account for CD40L's alloimmune effects and identified a therapeutic axis.

    Evidence Murine allograft model in CD40-/- hosts with CD154 mAb and a CD154:CD11b-specific peptide antagonist

    PMID:32149455

    Open questions at the time
    • Structural basis of CD154-CD11b binding not defined
    • Cell types where CD11b mediates CD154 effects not fully mapped
  18. 2022 High

    Showing P2Y12-dependent platelet CD40L release activates CD8+ T cells to suppress NAFLD-associated HCC, with CD40L-/- platelet transfusion failing to protect, established a beneficial anti-tumor arm of platelet CD40L and distinguished P2Y12 from aspirin-targeted pathways.

    Evidence NAFLD-HCC mouse model with P2Y12 inhibition/depletion, WT vs CD40L-/- platelet transfusion, and aspirin comparison

    PMID:36055226

    Open questions at the time
    • Cell expressing CD40 that receives the platelet CD40L signal to prime CD8+ T cells not pinpointed
    • Whether this extends beyond NAFLD-HCC context untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct CD40, integrin, and CD11b binding modes are differentially used across cell types and disease contexts, and how transcriptional, epigenetic, and 3'UTR-based controls are integrated to set CD40L dosage in vivo, remain unresolved.
  • No unified structural model of CD40L bound to non-CD40 receptors
  • Integration of the multiple regulatory layers in physiological settings unmapped
  • Relative in vivo contributions of T-cell vs platelet CD40L across diseases not systematically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-109582 Hemostasis 3 R-HSA-8953854 Metabolism of RNA 2
Partners
CD40ITGA5ITGAMITGAVITGB1ITGB3PTBP1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of the CD40-CD154 complex determined at 3.5 Å resolution. The CD40 binding site is located in a crevice formed between two CD154 subunits, with charge complementarity playing a critical role. CRD3 of CD40 has a disulfide bridge in an unusual position that alters its ladder-like structure. Missense mutations causing hereditary hyper-IgM syndrome map to the CD40-CD154 interface. The Ser132 loop of CD154 is not involved in CD40 binding but its substitution reduces p38- and ERK-dependent signaling without affecting JNK-dependent signaling, indicating that ligand-induced di/trimerization is necessary but not sufficient for complete CD40 activation. X-ray crystallography at 3.5 Å + site-directed mutagenesis + signaling assays The Journal of biological chemistry High 21285457
2019 Integrin α5β1 binds to CD40L at the trimeric interface of monomeric CD40L (distinct from the CD40 binding site). Mutations in the predicted integrin-binding site markedly reduced α5β1 binding and abrogated NF-κB activation and B cell activation, while retaining CD40 binding. Integrin αvβ3 also binds CD40L in a KGD-independent manner. Several HIGM1-associated missense mutations in CD40L cluster in the integrin-binding site and are defective in integrin (but not CD40) binding, suggesting integrin binding defects contribute to HIGM1. CD40L mutants defective in integrin binding act as antagonists of CD40/CD40L signaling. Docking simulation, binding assays with integrin mutants, NF-κB reporter assays, B cell activation assays Journal of immunology (Baltimore, Md. : 1950) Medium 31331973
1994 Defective expression of CD40L (TRAP) on activated T cells is responsible for X-linked hyper-IgM syndrome (HIGM1). Various mutations in the CD40L gene prevent T-cell CD40L from interacting with CD40 on B cells, causing failure of immunoglobulin isotype switching from IgM to IgG, IgA, and IgE. CD40L is not required for IgM synthesis but is a prerequisite for effective isotype switching in vivo. Genetic mapping, cDNA sequencing, mutation analysis, functional B-T cell interaction assays Immunological reviews High 7915248
2003 CD154 mRNA stability is regulated post-transcriptionally via a novel cis-acting instability element in a polypyrimidine-rich region of the CD154 3'UTR. Two major 3'UTR-binding proteins were identified as members of the polypyrimidine tract binding protein (PTB) family: PTB and a novel alternatively spliced isoform PTB-T. PTB-T decreases CD154 3'UTR-dependent expression while PTB tends to increase it, with their relative cytoplasmic levels determining mRNA accumulation. RNA pulldown and protein purification/sequencing, reporter gene assays (luciferase), tetracycline-responsive reporter for mRNA decay, cotransfection of PTB/PTB-T expression vectors Molecular and cellular biology High 12509450
1999 CD154 mRNA is highly unstable early after T cell activation but stability measurably increases after 24–48 h of activation. PMA+ionomycin greatly increased CD154 mRNA stability similar to its effect on TNF-α mRNA. CD28 costimulation only modestly increased stability. The pattern of CD154 mRNA stabilization is distinct from TNF-α and c-myc, indicating unique post-transcriptional regulation contributes to the temporal surface expression of CD154 on activated CD4+ T cells. mRNA decay assays in primary human CD4+ T cells activated with anti-CD3, PMA+ionomycin, or anti-CD3+anti-CD28; Northern blot and surface protein measurement over time course Journal of immunology (Baltimore, Md. : 1950) Medium 10201926
2001 CD40L is localized in the cytoplasm of resting platelets and is translocated to the platelet surface upon activation. Surface expression of CD40L is dependent on internal Ca2+ stores and protein kinase C, but not ERK, p38 MAPKs, or tyrosine kinases. Collagen at low concentrations (1–3 µg/ml) induces CD40L surface expression without inducing granule proteins (CD62P, CD63), indicating CD40L is stored in a distinct subcellular compartment. ADP-induced CD40L expression is abolished by clopidogrel treatment. Flow cytometry, immunofluorescence microscopy, Western blotting of subcellular platelet fractions, pharmacological inhibitors Platelets Medium 11297035
2007 CD40 engagement induces formation of disulfide-linked (dl) CD40 homodimers predominantly associating with detergent-resistant membrane microdomains. Mutagenesis revealed that cytoplasmic Cys238 of CD40 is the target for de novo disulfide oxidation induced by receptor oligomerization, and integrity of detergent-resistant membranes is required. dl-CD40 homodimer formation is required for CD40-induced IL-8 secretion and for IL-2 production by CD154-positive T cells in a bidirectional signaling model. Mutagenesis of Cys238, co-immunoprecipitation, detergent-resistant membrane fractionation, cytokine ELISAs, superantigen-stimulated T cell co-cultures The Journal of biological chemistry Medium 17504764
2004 Platelet-derived CD40L directly activates B lymphocytes via CD40-dependent signaling. Platelet-associated CD154 is increased in immune thrombocytopenic purpura (ITP) patients and is competent to induce CD40-dependent B lymphocyte proliferation. In vitro, platelet CD154 drives CD154-dependent production of anti-GPIIb/IIIa antibodies when co-cultured with peripheral blood B lymphocytes from ITP patients, demonstrating that platelet CD154 can activate autoreactive B cells. Flow cytometry, B cell proliferation assays, antibody production assays (co-culture of ITP patient platelets and B cells), RT-PCR of megakaryocyte CD154 mRNA Blood Medium 15191945
2006 Platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of T cell-expressed CD154. CD154-knockout mice rejected cardiac allografts after receiving CD154-expressing human platelets or recombinant trimeric CD154. Soluble trimers induced rejection when infused remote from surgery only when platelets were also surgically activated, indicating platelet activation is required for sufficient CD154 release. A human CD154-specific mAb (5c8) specifically prevented platelet-induced rejection. Murine cardiac allograft model with CD154-KO recipients, platelet transfusion experiments, recombinant CD154 trimer infusion, antibody neutralization The Journal of clinical investigation High 16498500
2009 Platelet-derived CD40L mediates sepsis-induced neutrophil Mac-1 upregulation and lung neutrophil recruitment indirectly via MIP-2 (CXCL2) formation and CXCR2 signaling, not through direct action on neutrophils. In CD40L-deficient mice, CLP-induced Mac-1 expression on neutrophils was abolished and lung edema, myeloperoxidase activity, and bronchoalveolar neutrophil infiltration were markedly reduced. Platelet depletion reduced CLP-induced CD40L levels by 90%, confirming platelets as the major source. CD40L-knockout mice, cecal ligation and puncture (CLP) model, platelet depletion with anti-GP1bα antibody, CXCR2 inhibition, flow cytometry, in vitro neutrophil stimulation Annals of surgery High 19806052
2004 CD154 (CD40L) expressed on endothelial cells is induced by CD40 engagement (not by TNF-α or IFN-γ alone). CD40-induced endothelial CD154 expression in turn activates transmigrating CD40+ monocytes, increasing their IL-1β mRNA and protein expression. This activation was abrogated by a neutralizing anti-CD154 antibody, demonstrating a CD154-dependent positive feedback loop in endothelial-monocyte inflammatory interactions. Primary human endothelial cell cultures, RT-PCR and Western blot for CD154, monocyte (THP-1) transmigration assay, IL-1β ELISA, neutralizing antibody blockade Arteriosclerosis, thrombosis, and vascular biology Medium 14976003
1999 CD154-CD40 ligation on human umbilical vein endothelial cells (HUVEC) induces production of specific chemokines: IL-8 (mediating neutrophil migration), MCP-1, and RANTES (mediating PBMC migration), but not MIP-1α. Enhanced leukocyte chemotaxis was specifically inhibited by anti-CD154 mAb. These effects were independent of IL-1β production. Jurkat-CD154+ co-culture with HUVEC, anti-CD154 mAb blockade, chemotaxis assays, anti-chemokine antibody neutralization, ELISA Cellular immunology Medium 10648122
2005 CD40 on platelets functions as a primary signaling receptor for CD40L, mediating platelet activation (increased CD62P expression) in a CD40-dependent manner. Recombinant trimeric soluble CD40L activates platelets through CD40. Additionally, CD40 serves as a docking molecule for CD40L immune complexes that subsequently activate platelets via FcγRII. CD40- and CD40L-deficient mice show prolonged tail bleeding times, indicating a role for the CD40-CD40L dyad in primary hemostasis. CD40/CD40L-deficient mice (tail bleeding assay), recombinant trimeric sCD40L stimulation, CD40 mAb blockade, flow cytometry for CD62P, chemical cross-linking, PFA-100 closure time assay Thrombosis and haemostasis Medium 15968400
2001 Glucocorticoid receptor activation by hydrocortisone (HC) upregulates CD40L mRNA and surface protein expression in PBMCs, T cells, and B cells, leading to CD40L-dependent IgE isotype switching. HC-induced IgE synthesis was abolished in CD40L-deficient patient B cells and blocked by anti-CD40L mAb or soluble CD40-Ig. Upregulation of CD40L mRNA occurred within 3 hours and was inhibited by actinomycin D and the glucocorticoid receptor antagonist RU-486, indicating transcriptional induction through the glucocorticoid receptor. CD40L-deficient patient cells, anti-CD40L mAb and soluble CD40-Ig blockade, RT-PCR, flow cytometry, RU-486 inhibition, actinomycin D transcription block The Journal of clinical investigation High 11160161
1998 IL-12 upregulates CD40L expression on anti-CD3-activated human peripheral blood T cells at both mRNA and protein levels. For optimal CD40L induction, IL-12 synergizes with IL-2 and B7/CD28 costimulatory signals. IL-12-enhanced T cell help for B cell proliferation and IgG production was blocked by anti-CD40L mAb, demonstrating that IL-12's effect on humoral responses is mediated indirectly through CD40L induction. T cell stimulation with anti-CD3 ± IL-12, flow cytometry for surface CD40L, RT-PCR for mRNA, B cell proliferation and IgG production assays, anti-CD40L mAb blocking Journal of immunology (Baltimore, Md. : 1950) Medium 9570530
2007 CD40LG on the inactive X chromosome is regulated by DNA methylation. In women, one CD40LG allele is methylated (on the inactive X) and one is unmethylated. Demethylation with 5-azacytidine doubled CD40LG expression on CD4+ T cells from women but not men. In women with lupus, CD40LG demethylates on the inactive X chromosome, leading to overexpression of CD40L on CD4+ T cells unique to women (not seen in male lupus patients). Bisulfite sequencing of CD40LG regulatory sequences, 5-azacytidine treatment of T cells, flow cytometry for CD40L surface expression, comparison between male and female patients Journal of immunology (Baltimore, Md. : 1950) Medium 17947713
2016 CD40L expression in CD8+ cytotoxic T cells is suppressed by epigenetic mechanisms including CpG methylation and histone H3K9, H3K27, and H4K20 methylation at the Cd40lg promoter. The transcription factor ThPOK (encoded by Zbtb7b) represses CXXC5 expression; CXXC5 associates with SUV39H1 to induce H3K9 methylation at the Cd40lg promoter. ThPOK retroviral transduction into CD8+ T cells induced moderate CD40L expression accompanied by reduced H3K9 and H3K27 methylation at the Cd40lg promoter. ChIP assays for histone modifications at Cd40lg promoter, retroviral ThPOK transduction into CD8+ T cells, CXXC5 transgene experiments, SUV39H1 co-immunoprecipitation Journal of leukocyte biology Medium 26896487
1999 CD40-CD40L interactions in atherosclerosis were demonstrated to be important in late atherosclerotic changes. Genetic disruption of CD154 in ApoE-/- mice reduced plaque area by ~550% compared to ApoE-/- controls. Advanced plaques in CD154-/-ApoE-/- mice had a collagen-rich, stable phenotype with reduced lipid core, T-lymphocyte content, and macrophage content, demonstrating that CD40-CD154 signaling drives lipid core formation and plaque destabilization. CD154 knockout in ApoE-/- mice, quantitative plaque morphometry, immunohistochemistry for plaque composition Nature medicine High 10546000
2005 CD154-CD40 pathway drives hepatocyte apoptosis in murine fulminant hepatitis. CD154-deficient mice show attenuated con A hepatitis with decreased hepatic TNF-α and hepatocyte death. In vitro, TNF-α induces CD40 expression on hepatocytes, and subsequent CD40 activation induces hepatocyte apoptosis mediated at least in part by enhanced FasL expression on hepatocytes. CD154-knockout mice in con A hepatitis model, in vitro hepatocyte culture with TNF-α and CD40 stimulation, apoptosis assays, FasL expression measurement Hepatology (Baltimore, Md.) Medium 16025512
2020 CD11b (Mac-1) functions as a novel receptor for CD154 during alloimmunity. CD154 blockade was more effective than CD40 blockade in prolonging allograft survival and reducing graft-infiltrating CD8+ T cells even in CD40-/- hosts. A specific peptide antagonist blocking CD154-CD11b interactions (without affecting CD154-CD40 interactions) significantly increased efficacy of anti-CD40 in prolonging allograft survival, reduced graft-infiltrating CD8+ T cells and innate immune cells. Combined blockade of both CD40 and CD11b interactions is required for optimal inhibition of alloimmunity. Murine allograft model with CD40-/- hosts, CD154 blockade with anti-CD154 mAb, CD154:CD11b-specific peptide antagonist, flow cytometry for graft-infiltrating cells American journal of transplantation Medium 32149455
1999 B cells in germinal centers express CD154. B cell CD154 expression is induced by surface Ig or CD40 engagement via AP-1/NF-AT and NF-κB, respectively. Anti-CD154 mAb inhibited differentiation of germinal center B cells to memory B cells and inhibited B cell proliferation. CD154 itself functions as a direct signaling molecule on B cells: anti-CD154-conjugated Sepharose beads costimulated B cell responses induced by surface Ig engagement. Immunohistochemistry and flow cytometry of tonsillar B cells ex vivo, in vitro B cell stimulation, anti-CD154 mAb blockade, CD154-Sepharose bead signaling assays Journal of immunology (Baltimore, Md. : 1950) Medium 10510350
2014 CD40L deficiency impairs selection of immunoglobulin reactivity and somatic hypermutation quality in human B cells. CD40L-deficient patients have reduced activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2) activity, less somatic hypermutation in class-switched transcripts, reduced IgM-distal isotype usage (IgG2, IgA2), and impaired selection against autoreactive antibodies. CD40 signaling is required for transcriptional regulation of DNA repair genes during somatic hypermutation. Flow cytometry on blood B cell subsets, molecular analysis of Ig transcripts, somatic hypermutation analysis, B cell activation assays in CD40L-deficient patients vs. controls The Journal of allergy and clinical immunology Medium 24418477
2012 Periodontopathogens (A. actinomycetemcomitans, P. gingivalis) directly induce surface expression and release of CD40L on human platelets via TLR2 and TLR4 signaling (requiring plasma CD14). This activation is completely abolished by inhibition of PI3K and PLC. TLR2 and TLR4 agonists also independently induce CD40L expression and release from platelets. Human platelet stimulation with periodontopathogens, flow cytometry for surface CD40L, ELISA for sCD40L, TLR2/TLR4 specific agonists, PI3K and PLC inhibitors, FcγRII blocking Thrombosis research Medium 22608210
2016 CD154 (CD40L) induces MMP-9 production in human podocytes via CD40/CD154 signaling. CD40 expression is acquired during podocyte differentiation and is enhanced upon exposure to recombinant CD154. Activated platelet supernatants induced MMP-9 mRNA in podocytes, and this effect was reduced by anti-CD40 antibody. CD154 thus regulates glomerular basement membrane remodeling through MMP-9. Human podocyte cultures with recombinant CD154, RT-PCR, Western blot, gelatin zymography for MMP-9, anti-CD40 antibody blocking, immunohistochemistry of kidney sections Journal of cellular biochemistry Medium 27070919
2022 Platelet anti-tumor function against HCC in NAFLD is mediated through P2Y12-dependent CD40L release, which activates CD8+ T cells via the CD40 receptor on other cells. Pharmacological P2Y12 inhibition and genetic depletion of P2Y12 abolished this effect. Transfusion of CD40L-/- platelets (vs. WT platelets) failed to suppress HCC growth. Aspirin, unlike P2Y12 inhibition, did not prevent platelet CD40L release and did not accelerate HCC. NAFLD-HCC mouse model, P2Y12 inhibitor treatment, P2Y12 genetic depletion, in vivo transfusion of WT vs. CD40L-/- platelets, aspirin treatment comparison Cancer cell High 36055226
2009 Platelet CD40L activates astrocytes and microglia in hypertension. ADP-activated platelets induced sCD40L release and astrocyte/microglia activation (GFAP and Iba-1 expression). Recombinant CD40L directly induced NF-κB and MAPK inflammatory signaling in glia, resulting in neuroinflammation and neuronal apoptosis. Inhibition of platelet activation by clopidogrel or disruption of CD40 signaling prevented glial activation and provided neuroprotection in vivo. Injection of ADP-activated platelets into normotensive rats recapitulated glial activation in a CD40L-dependent manner. Rat hypertension model, in vitro platelet activation, platelet deposition measurement, recombinant CD40L stimulation, clopidogrel treatment, anti-CD40 antibody blockade, immunohistochemistry, flow cytometry Brain, behavior, and immunity Medium 27658543
2009 CD154 activates dendritic cells to produce IL-12p70. Adenoviral expression of hCD40L in human monocyte-derived DCs induced intracellular CD40L expression and IL-12p70 secretion. Co-treatment with IFN-γ substantially increased IL-12p70. Maturation cocktail containing PGE2 abolished IL-12p70 secretion unless combined with IFN-γ. Only DCs treated with Ad5hCD40L + maturation cocktail + IFN-γ showed both migratory capacity toward CCL19 and continued IL-12p70 secretion. Adenoviral vector transduction of human DCs, ELISA for IL-12p70, migration assay toward CCL19, CD8+ T cell priming assay against MelanA/MART-1 antigen Journal of immunotherapy Medium 19609245
2009 Activation-induced CD154 expression on apoptotic T cells determines whether immune tolerance or immunity is generated. Naive apoptotic cells induced tolerance; activated apoptotic cells expressing CD154 induced immunity. CD154-/- apoptotic T cells induced tolerance regardless of activation state. Dendritic cells fed activated apoptotic T cells produced IL-12p40 in a CD154-dependent manner, and IL-12 was required to convert tolerance to immunity. Agonistic anti-CD40 mAb mimicked CD154 in switching tolerance to immunity. Intravenous injection of naive vs. activated CD154-/- and WT apoptotic T cells, anti-CD40 agonistic mAb, IL-12p40-/- mice, IL-12 neutralizing mAb, in vitro DC-apoptotic T cell cultures with IL-12p40 ELISA Journal of immunology (Baltimore, Md. : 1950) Medium 19841180

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunological reviews 1282 19426221
1998 CD40 and CD154 in cell-mediated immunity. Annual review of immunology 1166 9597126
2001 The CD40/CD154 receptor/ligand dyad. Cellular and molecular life sciences : CMLS 610 11229815
2004 CD40/CD154 interactions at the interface of tolerance and immunity. Annual review of immunology 522 15032580
1999 Requirement for CD154 in the progression of atherosclerosis. Nature medicine 377 10546000
2007 Demethylation of CD40LG on the inactive X in T cells from women with lupus. Journal of immunology (Baltimore, Md. : 1950) 351 17947713
2009 The role of CD40 and CD154/CD40L in dendritic cells. Seminars in immunology 348 19524453
2018 Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Advanced drug delivery reviews 264 30552917
2000 CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 262 11049967
2001 Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 225 11297035
2020 Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacology & therapeutics 207 33091428
2003 The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine & growth factor reviews 150 12787567
2002 CD40-CD40L interactions in atherosclerosis. Trends in cardiovascular medicine 147 11796241
2004 Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 141 15230298
1996 Functions of CD40 and its ligand, gp39 (CD40L). Critical reviews in immunology 139 8809473
2004 The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 135 15621572
2009 CD40/CD40L signaling and its implication in health and disease. BioFactors (Oxford, England) 134 19904719
2003 Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia. Stroke 134 12764232
1994 Defective expression of CD40 ligand on T cells causes "X-linked immunodeficiency with hyper-IgM (HIGM1)". Immunological reviews 120 7915248
2022 Platelets as Key Factors in Inflammation: Focus on CD40L/CD40. Frontiers in immunology 118 35185916
2009 The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thrombosis and haemostasis 114 19652870
2011 The CD40-CD40L system in cardiovascular disease. Annals of medicine 112 21244217
2001 Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 108 11297266
2009 Platelet-derived CD40L (CD154) mediates neutrophil upregulation of Mac-1 and recruitment in septic lung injury. Annals of surgery 101 19806052
2017 CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progression. Journal of immunology (Baltimore, Md. : 1950) 97 28455435
2017 CD40L and Its Receptors in Atherothrombosis-An Update. Frontiers in cardiovascular medicine 97 28676852
1997 CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 95 9422418
2000 CD154 (CD40 ligand). The international journal of biochemistry & cell biology 92 10856699
2004 Platelet-associated CD154 in immune thrombocytopenic purpura. Blood 91 15191945
2017 Functions of CD40 and Its Ligand, gp39 (CD40L). Critical reviews in immunology 90 29773027
2019 A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Science translational medicine 86 31019027
2011 Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation. The Journal of biological chemistry 86 21285457
2009 Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Advances in experimental medicine and biology 86 19760064
2005 The role of CD40 in CD40L- and antibody-mediated platelet activation. Thrombosis and haemostasis 83 15968400
1999 CD154 (CD40L) induces human endothelial cell chemokine production and migration of leukocyte subsets. Cellular immunology 81 10648122
2007 CD40/CD40L system and vascular disease. Internal and emergency medicine 77 18043876
2006 Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154. The Journal of clinical investigation 76 16498500
1997 The CD40-CD154 system in anti-infective host defense. Current opinion in immunology 73 9287184
2003 Delineation of a novel pathway that regulates CD154 (CD40 ligand) expression. Molecular and cellular biology 71 12509450
2024 Inhibition of CD40L with Frexalimab in Multiple Sclerosis. The New England journal of medicine 70 38354138
1998 IL-12 up-regulates CD40 ligand (CD154) expression on human T cells. Journal of immunology (Baltimore, Md. : 1950) 69 9570530
2022 Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD. Cancer cell 67 36055226
2004 CD154/CD40-mediated expression of CD154 in endothelial cells: consequences for endothelial cell-monocyte interaction. Arteriosclerosis, thrombosis, and vascular biology 67 14976003
2017 The CD40-CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Frontiers in immunology 66 29312317
2015 The Contribution of CD40/CD40L Axis in Inflammatory Bowel Disease: An Update. Frontiers in immunology 66 26528290
2018 Multiple effects of CD40-CD40L axis in immunity against infection and cancer. ImmunoTargets and therapy 65 29988701
1999 Regulation of CD154 (CD40 ligand) mRNA stability during T cell activation. Journal of immunology (Baltimore, Md. : 1950) 65 10201926
2009 The immunobiology of CD154-CD40-TRAF interactions in atherosclerosis. Seminars in immunology 64 19616449
2002 The CD154-CD40 costimulatory pathway in transplantation. Transplantation 62 11810060
2007 Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 61 18061473
2015 Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance. Immunotherapy 58 25917630
2001 Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching. The Journal of clinical investigation 58 11160161
1999 CD40-CD154 interaction in experimental and human disease (review). International journal of molecular medicine 56 10085405
2014 Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. The Journal of allergy and clinical immunology 54 24418477
1999 Expression of CD40 and its ligand, CD40L, in intestinal lesions of Crohn's disease. The American journal of gastroenterology 53 10566730
1993 CD40L: a multi-functional ligand. Seminars in immunology 53 7510138
2015 Update on CD40 and CD154 blockade in transplant models. Immunotherapy 52 26268734
2012 CD40 ligand (CD154) involvement in platelet transfusion reactions. Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine 52 22703674
2002 CD40-CD40L interaction in Alzheimer's disease. Current opinion in pharmacology 52 12127879
2001 The role of CD154 in organ transplant rejection and acceptance. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 52 11375072
2022 CD40-CD40L in Neurological Disease. International journal of molecular sciences 50 35456932
1994 The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. The Journal of clinical investigation 50 7518839
2019 Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling. Journal of immunology (Baltimore, Md. : 1950) 44 31331973
2016 Platelet CD40L induces activation of astrocytes and microglia in hypertension. Brain, behavior, and immunity 44 27658543
2004 The role of CD40-CD154 interaction in cell immunoregulation. Journal of biomedical science 44 15153777
2003 CD154 transcriptional regulation in primary human CD4 T cells. Immunologic research 44 12857968
2000 Immune regulation by CD40-CD40-l interactions - 2; Y2K update. Frontiers in bioscience : a journal and virtual library 42 11056083
1999 Expression, regulation, and function of B cell-expressed CD154 in germinal centers. Journal of immunology (Baltimore, Md. : 1950) 42 10510350
2009 CD154 and its receptors in inflammatory vascular pathologies. Trends in immunology 39 19282242
2010 Impact of the CD40-CD40L dyad in Alzheimer's disease. CNS & neurological disorders drug targets 38 20205645
2000 CD40L, but not CD40, is required for allergen-induced bronchial hyperresponsiveness in mice. American journal of respiratory cell and molecular biology 38 11062143
2018 Platelets Enhance Dendritic Cell Responses against Staphylococcus aureus through CD40-CD40L. Infection and immunity 36 29914928
2001 Increased T cell expression of CD154 (CD40-ligand) in multiple sclerosis. European journal of neurology 35 11422428
2001 Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy. Experimental hematology 35 11495701
2020 CD11b is a novel alternate receptor for CD154 during alloimmunity. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 34 32149455
2009 Generation of human dendritic cells that simultaneously secrete IL-12 and have migratory capacity by adenoviral gene transfer of hCD40L in combination with IFN-gamma. Journal of immunotherapy (Hagerstown, Md. : 1997) 34 19609245
2016 ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1: implications in repression of CD40L expression in CD8+ cytotoxic T cells. Journal of leukocyte biology 32 26896487
2023 CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation. Transplantation 31 36584382
2012 Periodontopathogens induce expression of CD40L on human platelets via TLR2 and TLR4. Thrombosis research 31 22608210
2009 Expression of CD40 and CD40L in gastric cancer tissue and its clinical significance. International journal of molecular sciences 31 19865524
2007 Requirement of oxidation-dependent CD40 homodimers for CD154/CD40 bidirectional signaling. The Journal of biological chemistry 31 17504764
2002 Expression of CD40 ligand (CD154) in B and T lymphocytes of Hodgkin disease: potential therapeutic significance. Cancer 31 11815953
1999 CD40L (CD154) expression in human liver allografts during chronic ductopenic rejection. Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 31 9873085
2019 Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis. Cells 30 31426619
1998 Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection. Pediatric transplantation 29 10084754
2005 CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology (Baltimore, Md.) 28 16025512
2015 New frontiers for platelet CD154. Experimental hematology & oncology 26 25763299
2015 Role of CD154 in cancer pathogenesis and immunotherapy. Cancer treatment reviews 26 25843228
2006 Immunotargeting with CD154 (CD40 ligand) enhances DNA vaccine responses in ducks. Clinical and vaccine immunology : CVI 26 16893998
2016 Levels of human platelet-derived soluble CD40 ligand depend on haplotypes of CD40LG-CD40-ITGA2. Scientific reports 25 27094978
2014 Platelets promote allergic asthma through the expression of CD154. Cellular & molecular immunology 25 25418472
2009 Hypoxia influences CD40-CD40L mediated inflammation in endothelial and monocytic cells. Immunology letters 25 19187784
2009 Post-transcriptional regulation in lymphocytes: the case of CD154. RNA biology 25 19395873
2020 The IL-33/ST2 pathway suppresses murine colon cancer growth and metastasis by upregulating CD40 L signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 32559854
2016 CD154 Induces Matrix Metalloproteinase-9 Secretion in Human Podocytes. Journal of cellular biochemistry 24 27070919
2010 The role of CD154 in haematopoietic development. Thrombosis and haemostasis 24 20694278
2021 CD40-CD154: A perspective from type 2 immunity. Seminars in immunology 23 34810089
2009 Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells. Journal of immunology (Baltimore, Md. : 1950) 23 19841180
2007 Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization. Blood 23 17827394
2004 Immunotherapy targeting the CD40/CD154 costimulatory pathway for treatment of autoimmune disease. Autoimmunity 23 15621565

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