title: An IL-12-independent role for CD40-CD154 in mediating effector responses: studies in cell-mediated glomerulonephritis and dermal delayed-type hypersensitivity.
abstract: Crescentic glomerulonephritis (GN) results from IL-12-driven Th1-directed cell-mediated responses (akin to delayed-type hypersensitivity (DTH)) directed against glomerular Ags. CD40-CD154 interactions are critical for IL-12 production and Th1 polarization of immune responses. Crescentic anti-glomerular basement membrane GN was induced in C57BL/6 (wild-type (WT)) mice (sensitized to sheep globulin) by planting this Ag (as sheep anti-mouse glomerular basement membrane globulin) in their glomeruli. Crescentic GN did not develop in CD40(-/-) mice due to significantly reduced nephritogenic Th1 responses. IL-12 was administered to CD40(-/-) mice with GN to dissect interactions between IL-12 and CD40 in inducing nephritogenic immunity and injury. Administration of IL-12 to CD40(-/-) mice restored Th cell IFN-gamma production, and up-regulated intrarenal chemokines and glomerular T cell and macrophage accumulation compared with WT control mice. Despite this, renal macrophages were not activated and renal injury and dermal DTH were not restored. Thus, CD40-directed IL-12 drives Th1 generation and effector cell recruitment but CD40 is required for activation. To test this hypothesis, activated OT-II OVA-specific CD4(+) cells and OVA(323-339)-loaded nonresponsive APCs were transferred into footpads of WT, CD40(-/-), and macrophage-depleted WT mice. WT mice developed significant DTH compared with CD40(-/-) and macrophage-depleted WT mice. This study demonstrated that CD40-induced IL-12 is required for generation of systemic Th1 immunity to nephritogenic Ags, and that IL-12 enhances Th1 effector cell recruitment to peripheral sites of Ag presentation via generation of local chemokines. Effector cell activation, renal DTH-like injury, and dermal DTH require direct Th1 CD154/macrophage CD40 interactions.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors.forename: Amanda-Jane
authors.initials: AJ
authors.lastname: Ruth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Semple
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Timoshanko
authors.forename: Peter G
authors.initials: PG
authors.lastname: Tipping
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D018925:Chemokines / Q000235:genetics; D005921:Glomerulonephritis / Q000209:etiology*; D006968:Hypersensitivity, Delayed / Q000209:etiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D019013:CD40 Antigens; D018925:Chemokines; D012333:RNA, Messenger; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma