Affinage

CD40

Tumor necrosis factor receptor superfamily member 5 · UniProt P25942

Round 2 corrected
Length
277 aa
Mass
30.6 kDa
Annotated
2026-04-28
130 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD40 is a TNF receptor superfamily member that functions as a master costimulatory receptor on B cells, dendritic cells, macrophages, and endothelial cells, coupling adaptive immune activation to vascular inflammation and antigen presentation. CD40 lacks intrinsic enzymatic activity and instead signals by recruiting TRAF adaptor proteins to two distinct cytoplasmic tail regions—TRAF2/3/5 bind residues 246–269 and TRAF6 binds residues 230–245—with trimeric receptor assembly as the minimal signaling unit that activates NF-κB, JNK/SAPK, p44/42 MAPK, and AKT pathways (PMID:7533327, PMID:8910514, PMID:11562359, PMID:10411888). Functionally, CD40 ligation drives B-cell proliferation and immunoglobulin class switching, upregulates B7 costimulatory molecules on antigen-presenting cells to license T-cell priming, sustains dendritic cell survival via Bcl2l1 induction, and activates endothelial cells to express adhesion molecules and angiogenesis factors; the TRAF6 axis specifically governs vascular inflammatory remodeling (PMID:7516669, PMID:8791591, PMID:36271147, PMID:7540655, PMID:18195092). Deficiency of its ligand CD40L causes X-linked hyper-IgM syndrome, and alternative splicing of CD40 pre-mRNA generates non-signaling isoforms that attenuate cellular responsiveness (PMID:7516669, PMID:11172023).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1986 High

    Identification of CD40 (Bp50) as a B-cell surface molecule that delivers costimulatory activation signals established the gene's foundational role in B-cell biology, distinguishing it from surface immunoglobulin.

    Evidence Monoclonal antibody stimulation of purified tonsillar B cells with cell-cycle analysis

    PMID:3487090

    Open questions at the time
    • Molecular identity and sequence unknown
    • Signaling mechanism uncharacterized
    • Expression on non-B cells not investigated
  2. 1989 High

    Molecular cloning of CD40 revealed homology to the nerve growth factor receptor, placing it in what became the TNF receptor superfamily and predicting a cytoplasmic signaling tail without intrinsic kinase activity.

    Evidence cDNA cloning and sequence analysis with transition matrix homology method

    PMID:2475341

    Open questions at the time
    • Ligand not yet identified
    • Downstream signaling adaptors unknown
    • Function of cytoplasmic tail not tested
  3. 1994 High

    Functional studies established that CD40–CD40L interactions drive immunoglobulin class switching, germinal center formation, and memory B-cell generation in vivo, and that CD40L deficiency causes X-linked hyper-IgM syndrome, defining CD40 as essential for humoral immunity.

    Evidence In vivo anti-CD40L antibody blockade in mice, adoptive transfer, B-cell culture with recombinant CD40L and cytokines, human genetics

    PMID:7516405 PMID:7516669

    Open questions at the time
    • Intracellular signal transduction pathway unresolved
    • Role in non-lymphoid tissues unclear
  4. 1995 High

    Discovery that TRAF2 directly binds the CD40 cytoplasmic tail and mediates NF-κB activation identified the first signal-transduction mechanism downstream of CD40, explaining how a receptor without intrinsic kinase activity signals.

    Evidence Yeast two-hybrid, dominant-negative TRAF2 overexpression blocking CD40-induced CD23 and NF-κB reporter activation

    PMID:7533327 PMID:7544915

    Open questions at the time
    • Binding sites for other TRAF family members not mapped
    • In vivo relevance of individual TRAFs untested
  5. 1995 High

    Demonstration that CD40 is expressed and functional on vascular endothelial cells—where ligation induces E-selectin, VCAM-1, and ICAM-1—extended CD40 biology beyond the immune system into vascular inflammation.

    Evidence Flow cytometry, recombinant CD40L stimulation, adhesion assays on human endothelial cells

    PMID:7538666 PMID:7540655

    Open questions at the time
    • Relative contribution of TRAF pathways in endothelial vs. immune cells unknown
    • In vivo vascular consequences not yet tested
  6. 1996 High

    Mapping of TRAF6 to a distinct cytoplasmic domain region (residues 230–245, separate from TRAF2/3/5 at 246–269) revealed that CD40 engages two parallel TRAF signaling axes, each activating NF-κB through different mechanisms.

    Evidence Yeast two-hybrid deletion analysis and NF-κB reporter assays

    PMID:8910514

    Open questions at the time
    • Functional distinction of TRAF6 vs. TRAF2/3/5 pathways in vivo not delineated
    • Structural basis of TRAF6 recognition unknown
  7. 1996 High

    CD40 signaling on antigen-presenting cells was shown to upregulate B7 costimulatory molecules, providing the mechanistic link by which CD40L-expressing T helper cells license dendritic cells and macrophages for T-cell priming.

    Evidence CD40L-deficient mouse reconstitution with agonistic anti-CD40 antibody, anti-B7 blockade

    PMID:8791591

    Open questions at the time
    • Downstream survival signals in DCs not characterized
    • Relative contribution of CD80 vs. CD86 unclear
  8. 1998 High

    In vivo antibody blockade of CD40L dramatically reduced atherosclerotic lesion formation in hyperlipidemic mice, establishing a causal role for the CD40–CD40L axis in atherogenesis beyond its immune functions.

    Evidence Anti-CD40L treatment in LDL-receptor KO mice on high-cholesterol diet with morphometry and immunohistochemistry

    PMID:9671306

    Open questions at the time
    • Whether CD40 on immune cells or vascular cells drives atherogenesis not resolved
    • Relative contribution of TRAF6 vs. TRAF2/3/5 in atherogenesis untested
  9. 1999 High

    The crystal structure of the TRAF2–CD40 peptide complex at 2.4 Å revealed the trimeric mushroom-shaped TRAF2 architecture and showed that each TRAF monomer rim binds one CD40 peptide in an extended conformation, providing the structural basis for ligand-induced receptor trimerization as the minimal signaling unit.

    Evidence X-ray crystallography at 2.4 Å resolution

    PMID:10411888

    Open questions at the time
    • Full-length receptor–TRAF complex structure unavailable
    • Dynamics of signalosome assembly not captured
  10. 2001 High

    Reconstitution experiments with soluble trimeric CD40 cytoplasmic domains showed that trimerization is sufficient for NF-κB activation and that the signaling complex contains TRAF2, TRAF3, TRAF5, TRAF6, and c-IAP1, defining the complete core signalosome composition.

    Evidence Myristoylated multimeric CD40 cytoplasmic domain constructs, immunoprecipitation, NF-κB reporter assay

    PMID:11562359

    Open questions at the time
    • Stoichiometry of TRAF molecules per CD40 trimer unknown
    • Post-translational modifications of TRAFs in the complex not characterized
  11. 2001 Medium

    Alternative splicing of CD40 pre-mRNA was found to generate non-signaling isoforms that accumulate during macrophage/DC activation, revealing a cell-intrinsic negative feedback mechanism that limits CD40 responsiveness over time.

    Evidence RT-PCR and IL-12 p40 reporter assay in macrophages and DCs transfected with individual isoforms

    PMID:11172023

    Open questions at the time
    • Splicing factors controlling the switch not identified
    • In vivo relevance of isoform ratio not demonstrated
    • Whether isoforms act as dominant negatives at the cell surface or intracellularly not resolved
  12. 2002 High

    The TRAF6–CD40 crystal structure revealed a Pro-X-Glu-X-X-(aromatic/acidic) binding motif oriented 40° differently from TRAF2 peptide binding, providing the structural explanation for why TRAF6 engages a distinct CD40 cytoplasmic domain and enabling design of TRAF6-blocking peptides.

    Evidence X-ray crystallography of TRAF6–CD40 peptide complex, cell-permeable peptide inhibition

    PMID:12140561

    Open questions at the time
    • Whether peptide inhibitors are selective in vivo unknown
    • Cooperativity between TRAF2/3/5 and TRAF6 binding on the same receptor trimer not addressed
  13. 2004 High

    Genetic epistasis using Act1-KO and Act1/CD40 double-KO mice identified Act1 as a negative regulator of CD40 signaling that restrains NF-κB processing, JNK, ERK, and p38 activation in B cells, establishing a cell-intrinsic brake on CD40 pathway output.

    Evidence Act1-KO and Act1/CD40 double-KO B-cell signaling assays

    PMID:15485634

    Open questions at the time
    • Mechanism by which Act1 inhibits TRAF signaling not defined
    • Act1 relevance in non-B-cell CD40 contexts untested
  14. 2007 High

    CD40L was shown to interact directly with integrin Mac-1 independently of CD40, mediating inflammatory cell adhesion and migration; Mac-1 inhibition—but not CD40 deficiency—attenuated atherosclerosis in vivo, revealing that some CD40L-driven vascular inflammation is CD40-independent.

    Evidence Multiple binding assays (flow cytometry, radioactive binding, co-IP) plus CD40-KO and Mac-1 inhibition in LDL-receptor KO mice

    PMID:17372166

    Open questions at the time
    • Relative contribution of Mac-1 vs. α5β1 integrin in CD40L-independent signaling not compared
    • Whether CD40L simultaneously engages CD40 and integrins on the same cell not tested
  15. 2008 High

    Transgenic mice carrying CD40 with site-specific TRAF6-binding mutations phenocopied CD40-KO in neointima formation, while TRAF2/3/5-binding mutations did not, establishing the TRAF6 axis as the critical mediator of CD40-driven vascular inflammatory remodeling.

    Evidence TRAF-binding site mutant CD40 transgenic mice, carotid ligation model, bone marrow reconstitution

    PMID:18195092

    Open questions at the time
    • Whether TRAF6 pathway dominance is specific to vascular cells or generalizable not resolved
    • Downstream effectors of TRAF6 in vascular remodeling not fully mapped
  16. 2014 Medium

    NEDD4 was identified as a constitutive CD40-associated E3 ubiquitin ligase that K63-ubiquitinates TRAF3, a modification required for CD40-mediated AKT activation and AID-dependent immunoglobulin class switching, adding a ubiquitin-dependent branch to CD40 signaling.

    Evidence Co-immunoprecipitation, K63-linkage-specific ubiquitination assay, AKT activation and class-switch analysis

    PMID:25072696

    Open questions at the time
    • Whether NEDD4 also modifies other CD40-associated TRAFs not tested
    • Structural basis of NEDD4–CD40 interaction unknown
    • In vivo confirmation in NEDD4-conditional KO not performed
  17. 2022 High

    Conditional deletion of CD40 in cDC1s revealed that CD40 sustains dendritic cell survival during anti-tumor T-cell priming by inducing Bcl2l1 (Bcl-xL), which maintains mitochondrial potential and blocks caspase activation—directly linking CD40 signaling to DC longevity in the tumor microenvironment.

    Evidence cDC1-specific Cre-driven CD40 KO, mitochondrial potential and caspase assays, Bcl2l1 reconstitution rescue

    PMID:36271147

    Open questions at the time
    • Whether Bcl2l1 induction operates through TRAF2/3/5 or TRAF6 not determined
    • Relevance to non-tumor inflammatory DC survival unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of full-length CD40 signalosome assembly beyond peptide-level TRAF interactions; the cell-type-specific logic that determines TRAF6 vs. TRAF2/3/5 pathway dominance; the splicing regulators controlling non-signaling CD40 isoform production; and whether simultaneous CD40L engagement of CD40 and integrins on the same cell creates composite signaling outputs.
  • Full-length receptor–TRAF signalosome structure not solved
  • Cell-type-specific TRAF pathway selection mechanism unknown
  • Splicing factors regulating CD40 isoform switching not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BIRC2CD40LGNEDD4TRAF2TRAF3TRAF3IP2TRAF5TRAF6

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 CD40 (Bp50) is a 50-kDa cell-surface molecule on all B cells that delivers activation signals promoting B-cell progression through the cell cycle; anti-Bp50 monoclonal antibody augments proliferation of activated B cells but does not activate resting B cells alone, distinguishing it functionally from Bp35 (surface Ig). Monoclonal antibody stimulation assays on purified tonsillar B cells; cell-cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 3487090
1989 CD40 (Bp50/CDw40) encodes a B-lymphocyte activation molecule whose predicted sequence shares extensive homology with the nerve growth factor receptor, placing it in the TNF receptor superfamily; its mRNA is induced by gamma-interferon in B cells and carcinomas. cDNA cloning, sequence analysis with transition matrix method, Northern blot The EMBO journal High 2475341
1990 IL-6 induces phosphorylation of CD40 in B cells through a mechanism requiring an intact CD40 cytoplasmic tail (including threonine-234), and conversely, CD40 ligation induces IL-6 production; this cross-talk requires functional CD40 but CD40 is not an IL-6 receptor. Mutagenesis of CD40 cytoplasmic tail (tailless and T234A mutants), growth inhibition assays, phosphorylation assays in M12 transformants Journal of immunology Medium 1696597
1994 CD40 is a 45–50 kDa glycoprotein of 277 amino acids; its gene maps to human chromosome 20q11.2–q13.2. CD40 ligation drives B-cell proliferation, isotype switching (to IgE with IL-4/IL-13, to IgG3/IgG1/IgA1 with IL-10), and generation of long-term B-cell lines. Deficiency of CD40L underlies X-linked hyper-IgM syndrome. Biochemical characterization, gene mapping, B-cell culture assays with recombinant CD40L and cytokines Annual review of immunology High 7516669
1994 gp39 (CD40L)–CD40 interactions are required for germinal center formation and generation of antigen-specific memory B cells in vivo; anti-gp39 antibody treatment completely abolished splenic germinal centers and blocked memory B-cell generation in adoptive transfer experiments. In vivo antibody blockade, immunohistochemistry, adoptive transfer experiments in mice The Journal of experimental medicine High 7516405
1994 Cyclosporin A (CsA) inhibits CD40L expression on T lymphocytes through calcineurin-dependent signaling: optimal CD40L expression requires protein kinase C activation and a rise in intracellular calcium; CsA inhibited IL-4-driven, CD40L-dependent IgE isotype switching. CsA analog dose-response correlating with calcineurin inhibition, T-cell activation assays, IgE switching assay The Journal of clinical investigation Medium 7907604
1995 TRAF2 (via CRAF1) directly binds the CD40 cytoplasmic tail through a shared TRAF-C domain that is necessary and sufficient for both CD40 binding and homodimerization; overexpression of a truncated CRAF1 inhibited CD40-mediated upregulation of CD23, identifying TRAF proteins as CD40 signal transducers. Yeast two-hybrid screen, dominant-negative overexpression, CD23 upregulation assay Science High 7533327
1995 TRAF2-mediated NF-κB activation is a common signaling output of TNF-R2 and CD40; overexpression of TRAF2 is sufficient to induce NF-κB activation, and a dominant-negative TRAF2 (lacking the RING finger domain) blocks NF-κB activation by both receptors. Overexpression and dominant-negative experiments, NF-κB reporter assay Science High 7544915
1995 CD40 is expressed on vascular endothelial cells and is upregulated by inflammatory agents; ligation by soluble gp39 (CD40L) activates endothelial cells to express E-selectin, ICAM-1, and augments VCAM-1 expression, promoting leukocyte adhesion. Flow cytometry, soluble recombinant CD40L stimulation, antibody blockade, adhesion assays, immunohistochemistry of inflammatory skin tissue The Journal of experimental medicine High 7540655
1995 CD40 is expressed on human umbilical vein endothelial cells and upregulated ~3-fold by TNF, IL-1, IFN-β, or IFN-γ; CD40 ligation by trimeric CD40L increases expression of E-selectin, VCAM-1, and ICAM-1 on endothelial cells. Flow cytometry, cytokine stimulation, recombinant trimeric CD40L ligation, adhesion molecule quantitation Proceedings of the National Academy of Sciences of the United States of America High 7538666
1996 CD40L-dependent T cell activation occurs through CD40 signaling on antigen-presenting cells that upregulates B7 costimulatory molecules (B7.2); reconstitution of CD40L-deficient mice with an activating anti-CD40 antibody restored both cellular and humoral immunity, which was then blocked by anti-B7 antibodies. CD40L-deficient mouse model, anti-CD40 agonist antibody reconstitution, anti-B7 blockade Science High 8791591
1996 CD40L (gp39)-positive helper T cells are co-localized with CD40-bearing monocytes/macrophages in active multiple sclerosis lesions; anti-CD40L monoclonal antibody prevented and treated experimental allergic encephalomyelitis (EAE) in mice, identifying CD40-CD40L as a functional mediator of CNS inflammation. Immunohistochemistry of MS brain sections, in vivo antibody blockade in EAE mouse model Proceedings of the National Academy of Sciences of the United States of America High 8637903
1996 A novel protein TRAF5 (originally identified as CRAF1 relative) binds the CD40 cytoplasmic tail; TRAF5-deficient B cells show defects in proliferation and upregulation of CD23, CD54, CD80, CD86, and Fas in response to CD40 stimulation, and reduced Ig production with IL-4. Gene targeting (TRAF5-/- mice), B-cell stimulation assays, surface molecule expression analysis Proceedings of the National Academy of Sciences of the United States of America High 10449775
1996 CD40 on dendritic cells mediates T-lymphocyte activation in allogeneic mixed leukocyte reactions; cross-linking of CD40 on DCs markedly augments CD80 and CD86 expression, and CD40-CD40L co-stimulation of DCs has both CD80/CD86-dependent and -independent components. CD40-Ig fusion protein blockade, CD40L trimer cross-linking, MLR assay, flow cytometry European journal of immunology Medium 8647193
1997 Platelets express CD40L within seconds of activation in vitro and during thrombus formation in vivo; platelet CD40L induces endothelial cells to secrete chemokines and express adhesion molecules, initiating an inflammatory response at sites of vessel injury. Flow cytometry, immunofluorescence, intravital microscopy, endothelial cell stimulation assay Nature High 9468137
1997 IL-2-activated NK cells express CD40L and can kill CD40-expressing target cells through a CD40-dependent activation pathway; CD40L cross-linking on NK cells induces redirected cytolysis, and this pathway can be downregulated by MHC class I molecules on target cells. NK cell killing assays with CD40-transfected targets, anti-CD40 antibody blockade, CD40L cross-linking with redirected cytolysis The Journal of experimental medicine Medium 9182676
1997 CD40L is constitutively expressed by human vascular endothelial cells, smooth muscle cells, and macrophages (not only activated T cells); these cell types co-express CD40 and CD40L in atherosclerotic lesions, enabling autocrine/paracrine signaling. CD40L on SMCs and macrophages is biologically active, inducing B7.2 on B cells and proinflammatory cytokines in SMCs. RT-PCR, immunohistochemistry, flow cytometry, B7.2 induction assay, cytokine ELISA Proceedings of the National Academy of Sciences of the United States of America High 9050882
1998 CD40 signaling through CD40L-CD40 interactions is required for CTL priming by cross-presentation; signaling through CD40 on antigen-presenting cells can substitute for CD4+ T helper cell help in generating CD8+ cytotoxic T-cell responses. CD40L-deficient mice, agonistic anti-CD40 antibody reconstitution, CTL priming assays Nature High 9624004
1998 Anti-CD40L antibody treatment reduced atherosclerotic lesion size by 59% and lipid content by 79% in hyperlipidemic LDL-receptor-deficient mice, with significant decreases in macrophages (64%), T lymphocytes (70%), and VCAM-1 expression, establishing a causal role for CD40 signaling in atherogenesis in vivo. In vivo antibody blockade in LDL-receptor KO mice on high-cholesterol diet, morphometric analysis, immunohistochemistry Nature High 9671306
1996 TRAF6 binds a distinct region of the CD40 cytoplasmic domain (residues 230–245) that is separate from the TRAF2/3/5 binding site (residues 246–269); TRAF6 overexpression activates NF-κB, and its TRAF-C domain suppresses NF-κB activation triggered by CD40 lacking residues 246–277, indicating TRAF6 mediates a distinct CD40 signaling pathway. Yeast two-hybrid, deletion analysis, NF-κB reporter assay The Journal of biological chemistry High 8910514
1998 RIP2 (a novel serine/threonine kinase with a CARD domain) is a component of the CD40 signaling complex; RIP2 overexpression activates NF-κB (requiring intact kinase domain plus CARD) and induces cell death (via CARD alone); RIP2 interacts with TRAF1, TRAF5, and TRAF6 but not TRAF2/3/4. Co-immunoprecipitation, overexpression, mutational analysis, NF-κB reporter assay The Journal of biological chemistry Medium 9642260
1999 Crystal structure (2.4 Å) of the TRAF2 receptor-binding fragment complexed with a CD40 cytoplasmic domain peptide reveals that TRAF2 forms a mushroom-shaped homotrimer; the CD40 peptide binds in an extended conformation with every side chain contacting a complementary groove on each TRAF monomer rim; spacing of CD40 binding sites on the TRAF2 trimer supports a signaling mechanism in which trimeric ligands pre-organize receptors to simultaneously engage three TRAF monomers. X-ray crystallography at 2.4 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 10411888
2001 CD40 pre-mRNA is alternatively spliced to generate multiple isoforms; expression shifts from signal-transducible CD40 mRNA early in macrophage/DC activation to signal-nontransducible isoforms (accounting for ~50% of CD40 mRNA) at 24 h; three alternative isoforms can disable CD40 signaling, with the major isoform lacking the membrane-associated endodomain reducing full-length CD40 on the cell surface. RT-PCR, IL-12 p40 reporter assay for CD40 signaling, transfection of isoforms in macrophages and DCs Proceedings of the National Academy of Sciences of the United States of America Medium 11172023
2001 CD40 mRNA and protein are expressed by neuronal cells and are upregulated during differentiation; CD40 ligation in neuronal cells activates p44/42 MAPK and opposes JNK phosphorylation induced by NGF withdrawal, protecting neurons from injury; adult CD40-deficient mice show neuronal dysfunction with decreased neurofilament isoforms, reduced Bcl-xL:Bax ratio, and increased DNA fragmentation. RT-PCR, Western blot, immunofluorescence, MAPK activation assays, JNK assay, CD40 KO mouse analysis The EMBO journal Medium 11847112
2001 AKNA, an AT-hook transcription factor, directly binds A/T-rich regulatory elements in the promoters of both CD40 and CD40L and coordinately regulates their expression; AKNA is a nuclear protein with PEST motifs expressed by germinal center B lymphocytes, T cells, NK cells, and DCs. Promoter binding assay, transfection, reporter gene assay, nuclear localization studies Nature Medium 11268217
2001 Act1 is a novel adaptor molecule that negatively regulates CD40 and BAFFR signaling; Act1-deficient B cells show significantly increased survival with stronger IκB phosphorylation, enhanced p100/p52 NF-κB2 processing, and augmented JNK, ERK, and p38 activation following CD40 stimulation; the B-cell phenotype in Act1-KO mice was largely rescued by double KO with CD40. Genetic knockout, double-knockout epistasis, B-cell signaling assays (NF-κB, MAPK pathways) Immunity High 15485634
2002 Crystal structures of TRAF6 alone and in complex with TRAF6-binding peptides from CD40 (and TRANCE-R) reveal a Pro-X-Glu-X-X-(aromatic/acidic) binding motif that differs fundamentally from TRAF2 peptide recognition (40° difference in bound peptide direction); cell-permeable peptides with this motif inhibit TRAF6 signaling. X-ray crystallography of TRAF6-CD40 peptide complex, cell-permeable peptide inhibition assay Nature High 12140561
2001 Soluble trimeric CD40 cytoplasmic domain constructs associate in complexes containing TRAF2, TRAF3, TRAF5, TRAF6, and c-IAP1; c-IAP1 association with the CD40 complex is indirect and dependent on an intact TRAF1/2/3 binding site; trimeric (but not monomeric) CD40 cytoplasmic domain is sufficient to activate NF-κB, indicating receptor trimerization is the minimal signaling unit. Soluble and myristoylated multimeric CD40 cytoplasmic domain constructs, immunoprecipitation, NF-κB reporter assay, point mutation analysis The Journal of biological chemistry High 11562359
2003 CD40 ligation on human endothelial cells induces expression of multiple angiogenesis factors including FGF-2, Flt-1, and Flt-4 in vitro; injection of CD40L-expressing fibroblasts into human skin grafts on SCID mice elicited angiogenesis factor expression and marked angiogenesis in vivo, which was abrogated by anti-VEGF, establishing a VEGF-dependent proangiogenic function of CD40 ligation. Anti-CD40 antibody stimulation of cultured ECs, in vivo SCID mouse skin graft model with CD40L-transfected fibroblasts, anti-VEGF blockade Journal of immunology Medium 12874247
2003 CD40 ligation stimulates antigen processing by B cells, enhancing MHC class II-restricted antigen presentation to T-cell hybrids; CD40 acts at an intracellular processing step (not peptide presentation per se) and independently of effects on B7, LFA-1, or CD23 expression or B-cell proliferation. B-cell/T-cell hybrid co-culture assay, recombinant CD40L-expressing insect cells, anti-CD40 mAb, peptide presentation controls European journal of immunology Medium 8566008
2003 CD154 (CD40L) mRNA stability is regulated by a novel cis-acting instability element in a polypyrimidine-rich region of the 3'UTR; polypyrimidine tract-binding protein (PTB) family members bind this element, with PTB-T decreasing and PTB stabilizing CD154 3'UTR-dependent expression, identifying a post-transcriptional pathway controlling CD40L levels. RNA-protein pulldown/purification, mass spectrometry identification, reporter gene with tet-inducible system, cotransfection of PTB isoforms Molecular and cellular biology Medium 12509450
2007 CD40L interacts directly with integrin Mac-1 (independently of CD40) via flow cytometry, radioactive binding assays, and immunoprecipitation, mediating Mac-1-dependent adhesion, migration, and myeloperoxidase release by inflammatory cells; CD40-deficient mice showed no reduction in atherosclerosis, whereas Mac-1 inhibition attenuated lesion development. Flow cytometry, radioactive binding assay, immunoprecipitation, in vitro adhesion/migration assays, CD40-KO and Mac-1 inhibition in LDL-receptor-KO mice Circulation High 17372166
2006 Soluble CD40L (sCD40L) binds to α5β1 integrin on monocytic cells independently of CD40 and αIIbβ3; direct binding of sCD40L to purified α5β1 was confirmed by solid-phase binding assay; sCD40L binding triggers translocation of α5β1 to detergent-insoluble fraction, rapid ERK1/2 MAPK activation, and IL-8 gene expression. Solid-phase binding assay with purified α5β1, antibody inhibition, ERK1/2 phosphorylation assay, IL-8 gene expression The Journal of biological chemistry Medium 17182621
2008 The CD40–TRAF6 signaling axis is the key regulator of neointima formation and vascular remodeling; CD40 KO mice showed reduced neointima formation with decreased inflammatory cell infiltration and matrix protease activity; mice carrying CD40 transgenes with mutations at TRAF6 binding sites (but not TRAF2/3/5 binding sites) phenocopied CD40 KO, identifying CD40-TRAF6 as the critical downstream pathway. CD40-/- mouse model, bone marrow reconstitution, transgenic mice with site-specific TRAF-binding mutations, carotid ligation model, intravital microscopy Blood High 18195092
2014 NEDD4 (an E3 ubiquitin ligase) constitutively interacts with CD40 and mediates K63-linked ubiquitination of TRAF3, which is required for CD40-mediated AKT kinase activation; NEDD4 also regulates immunoglobulin class switch by controlling activation-induced cytidine deaminase expression downstream of CD40. Co-immunoprecipitation, ubiquitination assay (K63-linkage specificity), AKT activation assay, class switch analysis Nature communications Medium 25072696
2015 Small molecules that block CD40–TRAF6 protein-protein interactions (identified by in silico docking and in vitro validation) reduce inflammation in peritonitis and sepsis mouse models without observed systemic side effects, validating the CD40-TRAF6 interface as a druggable target. In silico docking, in vitro binding assay, mouse models of peritonitis and sepsis Journal of chemical information and modeling Medium 25622654
2016 miR-145 inhibits vascular smooth muscle cell (VSMC) proliferation by directly targeting CD40; overexpression of miR-145 significantly inhibited CD40 expression and VSMC differentiation/proliferation induced by TNF-α, TGF-β, and homocysteine, and decreased IL-6 levels in VSMC supernatants. miR-145 overexpression, siRNA-mediated CD40 knockdown, proliferation assays, IL-6 ELISA Scientific reports Medium 27731400
2019 Staphylococcal superantigens (TSST-1, SEB, SEC) stimulate chemokine (IL-8, MIP-3α) production from human vaginal epithelial cells through CD40; CRISPR-Cas9 knockout of CD40 abolished this response, establishing CD40 as the receptor mediating superantigen-induced mucosal barrier disruption. CRISPR-Cas9 CD40 knockout, chemokine ELISA, superantigen stimulation assays mBio Medium 30890614
2022 CD40 signaling in classical type 1 dendritic cells (cDC1s) induces Bcl2l1 (Bcl-xL) expression, which sustains cDC1 survival (by maintaining mitochondrial transmembrane potential and suppressing caspase activation) during anti-tumor CD8 T-cell priming; cDC1-specific CD40 KO reduced migratory cDC1 numbers in tumor-draining lymph nodes, and this was reversed by Bcl2l1 re-expression. cDC1-specific Cre-driven CD40 KO, mitochondrial potential measurement, caspase activation assay, Bcl2l1 reconstitution, in vitro antigen presentation assay Nature immunology High 36271147
1999 CD40 stimulation inhibits Fas- and TNF-receptor-mediated apoptosis in hepatocellular carcinoma cells in a dose-dependent manner by blocking activation of CPP32 (caspase-3). Anti-CD40 antibody stimulation, apoptosis assays, Western blot for CPP32 activation Hepatology Medium 10498643
1998 CD40 associates with JAK3 kinase; however, studies of JAK3-deficient patients show that JAK3 is not essential for CD40-mediated B-cell proliferation, IgE isotype switching, or upregulation of CD23, ICAM-1, CD80, and LT-α. B-cell stimulation assays in JAK3-deficient patient samples versus normal controls Blood Medium 9746783

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2101 21833088
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
1998 CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1646 9468137
1998 Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1537 9624004
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 1127 10647992
1997 MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1121 9020361
1994 The CD40 antigen and its ligand. Annual review of immunology 1092 7516669
1997 The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO journal 1060 9384571
2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics 1018 20453842
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1995 TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science (New York, N.Y.) 938 7544915
1995 The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 885 7859281
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1998 Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 735 9671306
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1989 A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. The EMBO journal 594 2475341
1997 Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America 592 9050882
2002 Distinct molecular mechanism for initiating TRAF6 signalling. Nature 542 12140561
1996 Immune regulation by CD40 and its ligand GP39. Annual review of immunology 504 8717526
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