title: Requirement of oxidation-dependent CD40 homodimers for CD154/CD40 bidirectional signaling.
abstract: It is well established that the CD154/CD40 interaction is required for T cell-dependent B cell differentiation and maturation. However, the early molecular and structural mechanisms that orchestrate CD154 and CD40 signaling at the T cell/APC contact site are not well understood. We demonstrated that CD40 engagement induces the formation of disulfide-linked (dl) CD40 homodimers that predominantly associate with detergent-resistant membrane microdomains. Mutagenesis and biochemical analyses revealed that (a) the integrity of the detergent-resistant membranes is necessary for dl-CD40 homodimer formation, (b) the cytoplasmic Cys(238) of CD40 is the target for the de novo disulfide oxidation induced by receptor oligomerization, and (c) dl-CD40 homodimer formation is required for CD40-induced interleukin-8 secretion. Stimulation of CD154-positive T cells with staphylococcal enterotoxin E superantigen that mimics nominal antigen in initiating cognate T cell/APC interaction revealed that dl-CD40 homodimer formation is required for interleukin-2 production by T cells. These findings indicate that dl-CD40 homodimer formation has a physiological role in regulating bidirectional signaling.
authors.affiliation: Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier de l'Université Laval, Québec City, Québec G1V 4G2, Canada.
authors.forename: Carlos
authors.initials: C
authors.lastname: Reyes-Moreno
authors.forename: Ehssan
authors.initials: E
authors.lastname: Sharif-Askari
authors.forename: Julie
authors.initials: J
authors.lastname: Girouard
authors.forename: Claire
authors.initials: C
authors.lastname: Léveillé
authors.forename: Malek
authors.initials: M
authors.lastname: Jundi
authors.forename: Ali
authors.initials: A
authors.lastname: Akoum
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
authors.forename: André
authors.initials: A
authors.lastname: Darveau
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D019281:Dimerization; D004220:Disulfides / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology; D016296:Mutagenesis; D010084:Oxidation-Reduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; C508606:CXCL8 protein, human; D004220:Disulfides; D004768:Enterotoxins; D016209:Interleukin-8; C049463:enterotoxin E, Staphylococcal; D023201:CD40 Ligand