CD40 ligand (CD40L/CD154), encoded by CD40LG, is a type II transmembrane TNF-family protein displayed on activated T cells and platelets. Its extracellular domain binds CD40 on neighboring cells and initiates signaling that promotes immune-cell activation, B-cell proliferation and immunoglobulin class switching. Proteolytic processing also produces a biologically active soluble ligand. CD40L can engage selected integrins, and cross-linking membrane CD40L can transmit reverse costimulatory signals in T cells through associated signaling proteins. The principal physiological role is communication between activated T cells and CD40-bearing antigen-presenting cells; loss of CD40L function causes X-linked immunodeficiency with hyper-IgM.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002682 regulation of immune system process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: CD40L regulates immune-cell responses. Reason: The ARBA assignment is compatible with CD40 ligand-driven B-cell and T-cell responses, but this broad regulatory category adds little to the defined CD40 signaling function. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000117 | MODIFY | Summary: CD40 is an established signaling receptor bound by CD40L. Reason: The generic receptor-binding prediction can be replaced with the directly supported receptor-specific term; human TRAP/CD40L binding to a soluble CD40 construct was assayed. Proposed replacements: CD40 receptor binding Supporting Evidence: |
| GO:0005125 cytokine activity | IBA GO_REF:0000033 | ACCEPT | Summary: Soluble CD40L has cytokine activity. Reason: The PAINT IBA is compatible with the TNF-family ligand function and with directly assayed soluble human CD40L activity. P29965 in the descendant evidence is expected and is not circular. Cytokine activity here includes the cleaved soluble product; the membrane form also signals through cell contact. No PAINT node-placement challenge is made. |
| GO:0005125 cytokine activity | IDA PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | ACCEPT | Summary: CD40L is an extracellular immune-signaling ligand. Reason: The original paper describes platelet-surface CD40L inducing endothelial responses; its complete original assay was not inspected. Independently, soluble human CD40L drives B-cell proliferation, satisfying the cytokine-activity definition for that mature product. Retain the clearly supported gene-product function without re-describing the platelet experiment as a soluble-ligand assay. |
| GO:0005164 tumor necrosis factor receptor binding | IEA GO_REF:0000002 | MODIFY | Summary: CD40L binds the TNF-receptor-superfamily member CD40. Reason: The InterPro mapping captures the ligand family, but a receptor-specific molecular function is established experimentally for this protein. Proposed replacements: CD40 receptor binding Supporting Evidence: |
| GO:0005174 CD40 receptor binding | IMP PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | ACCEPT | Summary: Human CD40L directly binds CD40. Reason: The complete abstract of PMID:31331973 states simultaneous CD40/integrin binding and distinguishes integrin-site mutants that retain CD40 binding. This supports the receptor-binding assertion; detailed constructs and all figures were not inspected. Supporting Evidence: |
| GO:0005174 CD40 receptor binding | IPI PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | ACCEPT | Summary: CD40 is the cognate CD40L receptor. Reason: Preserve the exact P25942 supporting entity. The platelet/endothelial paper is consistent with this interaction, and independent human CD40L binding assays establish it. The original IPI experiment was not inspected beyond its abstract. |
| GO:0005178 integrin binding | IMP PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | KEEP AS NON CORE | Summary: CD40L binds selected integrin heterodimers. Reason: PMID:31331973 explicitly reports human CD40L binding to alpha5beta1 and alphavbeta3, with integrin-site mutations affecting binding and signaling. Retain this additional receptor interaction as non-core; do not generalize it to every integrin or equate the docking prediction with a solved interface. Independent soluble-CD40L experiments also support alphaIIbbeta3 binding in the platelet context. |
| GO:0005515 protein binding | IPI PMID:15067037 The modulation of CD40 ligand signaling by transmembrane CD2... | KEEP AS NON CORE | Summary: CD40L associates with the CD28i splice product. Reason: Full-text coimmunoprecipitation in digitonin extracts of transfected D1.1 cells and human peripheral-blood PHA blasts supports association with CD28i (CD28 isoform3). Wild-type CD28 was not associated in the reported normal-cell assay. The machine partner P10747 is retained, while the tested product context is recorded here. A weak receptor/adaptor complex does not establish a specific catalytic or adaptor activity of CD40L; retain generic binding under the project policy. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | MODIFY | Summary: CD40L binds alphavbeta3 integrin. Reason: The exact P06756/P05106 partners are the alphav/beta3 heterodimer. The original abstract explicitly reports this KGD-independent integrin interaction, permitting a more informative molecular-function label without inferring transport or catalytic activity. Proposed replacements: integrin binding Supporting Evidence: PMID:31331973 Integrin Ξ±vΞ²3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner |
| GO:0005515 protein binding | IPI PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | MODIFY | Summary: CD40L binds alpha5beta1 integrin. Reason: The exact P08648/P05556 partners form alpha5beta1. The original abstract reports binding and mutational effects; integrin binding is more informative than generic protein binding. Proposed replacements: integrin binding Supporting Evidence: PMID:31331973 Integrin Ξ±5Ξ²1 and CD40 simultaneously bind to CD40L. |
| GO:0005515 protein binding | IPI PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | MODIFY | Summary: CD40L binds its receptor CD40. Reason: The exact P25942 partner is CD40. The original abstract describes binding retained by several integrin-defective mutants, supporting the receptor-specific refinement. Proposed replacements: CD40 receptor binding Supporting Evidence: |
| GO:0005576 extracellular region | EXP PMID:8626375 Human native soluble CD40L is a biologically active trimer, ... | ACCEPT | Summary: The soluble CD40L product acts extracellularly. Reason: The original abstract directly reports soluble human CD40L cleavage products in stimulated T-cell supernatant. Supporting Evidence: |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: The soluble CD40L product acts extracellularly. Reason: The inherited extracellular location is supported by the cleaved soluble human product. The target in the PAINT descendant evidence is valid self-evidence, not circularity; the underlying node placement was not re-audited. Supporting Evidence: |
| GO:0005576 extracellular region | IDA PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | ACCEPT | Summary: The soluble CD40L product acts extracellularly. Reason: The original abstract establishes extracellular action of platelet-surface CD40L on endothelium; independent PMID:8626375 directly establishes a released soluble product. Retain extracellular activity without claiming the 1998 experiment characterized the secreted species. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: The soluble CD40L product acts extracellularly. Reason: The UniProt secreted-location mapping applies to cleaved soluble CD40L, not to every molecule of the membrane precursor. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:8626375 Human native soluble CD40L is a biologically active trimer, ... | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The primary report distinguishes transmembrane CD40L from its released soluble cleavage product. The location applies to the membrane form. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The immunofluorescence-derived localization is consistent with directly demonstrated cell-surface CD40L on human T cells; it is not evidence that the soluble mature product remains membrane anchored. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The UniProt cell-membrane mapping matches the type II single-pass membrane form. |
| GO:0005886 plasma membrane | TAS PMID:7678552 Human CD40-ligand: molecular cloning, cellular distribution ... | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The original human T-cell study reports FACS detection of CD40L at the cell surface and a type II membrane-protein sequence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-199404 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: Reactome models CD40L engagement of CD40 at the plasma membrane; primary human T-cell evidence independently supports the location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5668414 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The cited Reactome event describes TRAF2-dependent ubiquitination of cIAP proteins after receptor recruitment. It supplies pathway context for the membrane-associated ligand; CD40L is not the ubiquitin-transfer enzyme. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5668454 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: This event describes cIAP-mediated ubiquitination of TRAF3 downstream of receptor ligation. The location assertion is compatible with membrane CD40L initiating that signal, without assigning intracellular ligase activity to the ligand. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5668481 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: The event describes proteasome-dependent degradation of ubiquitinated TRAF3 and release of NIK. The source-derived membrane location agrees with direct CD40L surface evidence; CD40L does not perform the degradation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5676597 | ACCEPT | Summary: Membrane CD40L is displayed at the plasma membrane. Reason: This event describes recruitment of a TRAF-containing regulatory complex to the CD40 cytoplasmic tail after CD40L engagement. It is compatible with the membrane location of the external ligand and does not place CD40L in the intracellular TRAF complex. |
| GO:0006954 inflammatory response | IDA PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | KEEP AS NON CORE | Summary: Platelet CD40L promotes endothelial inflammation. Reason: The original abstract directly describes endothelial chemokine and adhesion-molecule induction by platelet CD40L. Retain this vascular inflammatory context separately from its principal T-cell/B-cell costimulatory role. Supporting Evidence: |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: CD40L participates in immune responses. Reason: The family-level InterPro assignment is biologically sound: CD40L supplies the receptor ligand that initiates immune-cell signaling and stimulates human B-cell responses, rather than serving only as a disease-associated marker. Supporting Evidence: |
| GO:0007154 cell communication | IEA GO_REF:0000117 | MODIFY | Summary: CD40L mediates intercellular CD40 signaling. Reason: The electronic cell-communication annotation is too broad to describe the established ligand/receptor mechanism. Use the experimentally supported CD40 pathway. Proposed replacements: CD40 signaling pathway |
| GO:0007159 leukocyte cell-cell adhesion | NAS PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | MODIFY | Summary: CD40L positively regulates leukocyte adhesion to activated endothelium. Reason: The original PMID9468137 abstract supports endothelial adhesion-molecule induction, while its detailed adhesion assays remain unverified. Independent PMID10929070 used soluble recombinant human CD40L to pretreat HUVEC and directly quantified adherent human leukocytes, demonstrating increased adhesion. Positive regulation therefore captures the demonstrated signaling role more precisely than attachment itself; this refinement neither asserts that the original source lacked an adhesion assay nor claims that CD40L cannot participate in other adhesive interactions. Proposed replacements: positive regulation of leukocyte cell-cell adhesion |
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: CD40L initiates cell-surface receptor signaling. Reason: The PAINT ancestral assignment agrees with direct human ligand binding and receptor-dependent signaling. This is an actual initiating step in the process, not inference from necessity alone. The PTN000895255 tree was not re-evaluated and no donor-count argument is used. |
| GO:0007229 integrin-mediated signaling pathway | IMP PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | KEEP AS NON CORE | Summary: Integrin engagement contributes to CD40L signaling in the tested systems. Reason: The original abstract links integrin-site mutation to impaired signaling while CD40 binding persists, supporting a role for integrin-dependent signaling. This does not demonstrate every downstream integrin pathway or make it the sole mechanism of CD40L activity. Supporting Evidence: |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The ligand domain of membrane CD40L faces the extracellular side. Reason: The mouse-derived localization inference matches the human type II topology and cell-surface receptor-binding role. The membrane form spans the bilayer; this external-side term refers to its extracellular ligand-bearing region rather than a secreted-only protein. |
| GO:0009986 cell surface | EXP PMID:7678552 Human CD40-ligand: molecular cloning, cellular distribution ... | ACCEPT | Summary: Membrane CD40L functions at the cell surface. Reason: The original cloning/distribution study directly reports surface detection on human T cells. Supporting Evidence: |
| GO:0009986 cell surface | IDA PMID:15067037 The modulation of CD40 ligand signaling by transmembrane CD2... | ACCEPT | Summary: Membrane CD40L functions at the cell surface. Reason: The full text reports CD40L surface staining and colocalization with CD28i; cross-linking induced coendocytosis. This supports surface localization without making endocytosis a core molecular function. Supporting Evidence: |
| GO:0009986 cell surface | IEA GO_REF:0000120 | ACCEPT | Summary: Membrane CD40L functions at the cell surface. Reason: The combined ARBA/UniProt mapping agrees with the established cell-surface membrane form. Supporting Evidence: |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: CD40L signaling changes downstream gene expression. Reason: The ARBA process assignment is compatible with receptor-dependent NF-kappaB activation and cytokine responses. It does not make CD40L a DNA-binding transcription factor or imply a direct nuclear activity. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The relevant membrane form is a plasma-membrane ligand. Reason: The broad membrane term can be refined using the directly supported human cell-surface location. Soluble cleavage products are handled by their separate extracellular annotations. Proposed replacements: plasma membrane Supporting Evidence: |
| GO:0016020 membrane | NAS PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | MODIFY | Summary: The relevant membrane form is a plasma-membrane ligand. Reason: The broad membrane term can be refined using the directly supported human cell-surface location. Soluble cleavage products are handled by their separate extracellular annotations. Proposed replacements: plasma membrane Supporting Evidence: |
| GO:0023035 CD40 signaling pathway | IDA PMID:1280226 Cloning of TRAP, a ligand for CD40 on human T cells. | ACCEPT | Summary: CD40L performs the ligand-recognition step that initiates CD40 signaling. Reason: The original human TRAP clone bound a soluble CD40 construct; complementary human functional assays establish subsequent B-cell responses. The ligand directly engages the receptor and therefore participates in this signaling pathway. |
| GO:0023035 CD40 signaling pathway | IMP PMID:31331973 Integrin Binding to the Trimeric Interface of CD40L Plays a ... | ACCEPT | Summary: Human CD40L binding drives CD40 pathway responses. Reason: Integrin-site mutants retained CD40 binding while losing efficient NF-kappaB and B-cell activation, demonstrating additional requirements for signaling in the tested model. The result supports pathway participation without assuming binding alone is sufficient for every response. Supporting Evidence: |
| GO:0023052 signaling | IEA GO_REF:0000117 | MODIFY | Summary: CD40 signaling is the defined pathway initiated by CD40L. Reason: The generic electronic signaling assignment can be refined to the directly established cognate receptor pathway. Proposed replacements: CD40 signaling pathway |
| GO:0030168 platelet activation | IDA PMID:9468137 CD40 ligand on activated platelets triggers an inflammatory ... | KEEP AS NON CORE | Summary: Soluble CD40L can act as a platelet agonist. Reason: The 1998 source abstract concerns activated-platelet CD40L acting on endothelium; its exact platelet-activation IDA assay remains unverified. Independent PMID:11875495 reports alphaIIbbeta3-dependent spreading and high-shear aggregation, while PMID:12676820 reports CD40-dependent granule and shape responses without aggregation. Retain the contextual function and original machine reference, with independent support rather than declaring the original citation erroneous. |
| GO:0031295 T cell costimulation | TAS PMID:8617933 Cross-linking of the CD40 ligand on human CD4+ T lymphocytes... | KEEP AS NON CORE | Summary: Cross-linking CD40L can supply a reverse costimulatory signal to T cells. Reason: The original human-cell abstract directly supports CD40L cross-linking in conjunction with CD3/TCR and CD28 ligation. This is ligand-side reverse signaling, distinct from forward activation of CD40 on the opposing cell. Retain as a supported additional signaling context. |
| GO:0032733 positive regulation of interleukin-10 production | IDA PMID:8617933 Cross-linking of the CD40 ligand on human CD4+ T lymphocytes... | UNDECIDED | Summary: The exact IL-10-production assay has not been verified. Reason: The accessible PMID:8617933 abstract directly documents IL-4, but does not expose the IL-10 experiment. UniProt and the introduction of PMID:15067037 repeat the broader cytokine claim; these are not independent inspection of the original IL-10 assay. The full original paper was inaccessible, so retain the assertion undecided rather than infer a citation error or substitute an IL-4 result. |
| GO:0032735 positive regulation of interleukin-12 production | IDA PMID:9922218 Interleukin-12 production by human alveolar macrophages is c... | UNDECIDED | Summary: CD40-triggered IL-12 production is established, but the cited CD40L-specific assay is unresolved. Reason: The cached abstract reports CD40 cross-linking plus IFN-gamma in human alveolar macrophages. Selected externally indexed Methods/Results text identifies anti-CD40 antibody immobilized on CD32-transfected cells. A complete primary-paper read was not obtained; this establishes a receptor-response context but does not verify a directly assayed CD40L ligand contribution. Preserve the original IDA and use UNDECIDED rather than claiming misattribution from an abstract. Supporting Evidence: |
| GO:0032753 positive regulation of interleukin-4 production | IDA PMID:8617933 Cross-linking of the CD40 ligand on human CD4+ T lymphocytes... | KEEP AS NON CORE | Summary: CD40L reverse costimulation enhances IL-4 production in human T cells. Reason: The primary abstract directly describes greater IL-4 production upon CD40L triggering with CD3/TCR and CD28 signals, including adult and cord-blood T cells. This is a supported, context-dependent cytokine-output process rather than CD40L itself synthesizing IL-4. Supporting Evidence: |
| GO:0042100 B cell proliferation | IDA PMID:8605945 Cleavage of membrane-bound CD40 ligand is not required for i... | MODIFY | Summary: CD40L positively regulates human B-cell proliferation. Reason: Soluble and uncleavable membrane human CD40L stimulate B-cell proliferation with IL-4. A positive-regulation term more precisely distinguishes this extracellular ligand function from the B cell division machinery; the original proliferation phenotype is retained, not rejected. Proposed replacements: positive regulation of B cell proliferation Supporting Evidence: |
| GO:0042102 positive regulation of T cell proliferation | IDA PMID:8617933 Cross-linking of the CD40 ligand on human CD4+ T lymphocytes... | UNDECIDED | Summary: The exact T-cell proliferation assay in the cited paper is not yet inspected. Reason: The complete accessible abstract establishes reverse costimulation and IL-4 production but does not expose the proliferation experiment. UniProt reports proliferation, but that is not an independent primary assay. Full text was inaccessible; preserve the IDA assertion and defer the source-specific decision. Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:12697681 CD40 ligand blocks apoptosis induced by tumor necrosis facto... | UNDECIDED | Summary: The cited study supports an anti-apoptotic CD40L response in bone-cell models. Reason: The abstract explicitly reports murine MLO-Y4 and osteoblast cell models and anti-apoptotic responses to added CD40L. The species and construct of the administered ligand are not established in the inspected abstract, and complete Methods were unavailable. The human IDA assertion is retained unresolved; the receiving cells being murine is not itself evidence that human ligand was absent or that the annotation is wrong. Supporting Evidence: |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: CD40L promotes NF-kappaB signaling. Reason: The conserved PAINT assignment is compatible with human ligand-induced NF-kappaB activation and with ligand-side reverse signaling. These pathways are not collapsed into a CD40L enzymatic activity. No challenge to PTN000895255 is made on donor-count grounds. |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:15067037 The modulation of CD40 ligand signaling by transmembrane CD2... | MARK AS OVER ANNOTATED | Summary: CD40L cross-linking induces downstream JNK and PAK2 activation, not a demonstrated direct kinase-activator activity. Reason: The full Methods/Results and Figure3 describe phospho-JNK/PAK2 immunoblots after anti-CD40L stimulation, with stronger responses upon CD28i expression. GO:0043539 specifically requires binding to and increasing serine/threonine-kinase activity. The paper demonstrates a signaling cascade and CD28i association, not CD40L binding a kinase and activating it as a molecular regulator. Mark the MF claim as over-annotated while retaining the measured reverse-signaling biology; this is not a claim that the kinase response is false. Supporting Evidence: PMID:15067037 JNK activation induced by CD40L stimulation was enhanced by the increased expression of CD28i-HA. |
| GO:0045190 isotype switching | IEA GO_REF:0000107 | MODIFY | Summary: CD40L promotes immunoglobulin isotype switching through B-cell receptor signaling. Reason: The conserved mouse-to-human function is well supported, including human CD40L-driven IgE responses. GO:0045190 defines the intrachromosomal switch-recombination process itself; the positive-regulation term more precisely describes the extracellular ligand that stimulates switching. This refines the role while preserving the biological effect and source ortholog. Proposed replacements: positive regulation of isotype switching |
| GO:0045190 isotype switching | ISS GO_REF:0000024 | MODIFY | Summary: CD40L promotes immunoglobulin isotype switching through B-cell receptor signaling. Reason: The conserved mouse-to-human function is well supported, including human CD40L-driven IgE responses. GO:0045190 defines the intrachromosomal switch-recombination process itself; the positive-regulation term more precisely describes the extracellular ligand that stimulates switching. This refines the role while preserving the biological effect and source ortholog. Proposed replacements: positive regulation of isotype switching |
| GO:2000353 positive regulation of endothelial cell apoptotic process | IDA PMID:12885753 A20 protects from CD40-CD40 ligand-mediated endothelial cell... | KEEP AS NON CORE | Summary: CD40L signaling can promote endothelial apoptosis under inflammatory conditions. Reason: The original abstract explicitly reports signaling through CD40L, endothelial apoptosis and inhibition by A20. This context-dependent response coexists with survival-promoting CD40L responses in other cell types; it is not a constitutive death-ligand function. Detailed original constructs and full text were not inspected. Supporting Evidence: |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CD40L can promote extrinsic apoptotic responses in selected contexts. Reason: Retain the PAINT process assignment as conditional rather than a defining death-ligand activity. Human endothelial evidence supports a pro-apoptotic signaling context, while CD40L also supports survival and immune activation elsewhere. The PTN000895255 node and MSA were not re-audited, and the donor list is not treated as weak merely because the target is not listed. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which original experiments in PMID:8617933 establish IL-10 production and T-cell proliferation, beyond the accessible IL-4/costimulation abstract?
Q: What ligand species and construct support the human CD40LG anti-apoptosis annotation from PMID:12697681, and was CD40L itself assayed in the IL-12 experiment attributed to PMID:9922218?
Q: Which physiological ligand configurations trigger CD28i-associated reverse signaling, and can direct CD40Lβkinase binding or activator activity be demonstrated separately from downstream phosphorylation?
Q: How do membrane versus soluble CD40L, integrin subtype and ligand oligomerization determine immune and platelet responses?
Experiment: Compare expression-matched membrane and purified soluble human CD40L, with CD40/integrin blockade and CD28i perturbation. Measure receptor binding separately from NF-kappaB, JNK/PAK2 phosphorylation and cell-type-specific outputs; use biochemical binding/activation assays before assigning intrinsic kinase-regulator activity.
Hypothesis: Ligand presentation and receptor composition determine whether CD40L elicits forward CD40 signaling, integrin-dependent responses or CD28i-associated reverse signaling.
Type: biochemical and cell-based signaling
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