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Title: | An IL-12-independent role for CD40-CD154 in mediating effector responses: Studies in cell-mediated glomerulonephritis and dermal delayed-type hypersensitivity. | Authors: | Timoshanko J.R.;Ruth A.-J.;Li M.;Semple T.J.;Tipping P.G.;Kitching A.R. ;Holdsworth S.R. | Institution: | (Ruth, Kitching, Li, Semple, Timoshanko, Tipping, Holdsworth) Department of Medicine, Monash University, Monash Medical Centre, Clayton, Vic., Australia (Holdsworth) Department of Medicine, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Vic. 3168, Australia | Issue Date: | 18-Oct-2012 | Copyright year: | 2004 | Publisher: | American Association of Immunologists (9650 Rockville Pike, Bethesda MD 20814, United States) | Place of publication: | United States | Publication information: | Journal of Immunology. 173 (1) (pp 136-144), 2004. Date of Publication: 01 Jul 2004. | 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 OVA323-339- 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. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.4049/jimmunol.173.1.136 | PubMed URL: | 15210767 [http://www.ncbi.nlm.nih.gov/pubmed/?term=15210767] | ISSN: | 0022-1767 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/32552 | Type: | Article | Subjects: | male mouse nonhuman priority journal sensitization *skin allergy/et [Etiology] adolescent Th1 cell immune injury/et [Etiology] macrophage macrophage activation antigen presenting cell article *cellular immunity controlled study cytokine production *delayed hypersensitivity/et [Etiology] effector cell *glomerulonephritis/et [Etiology] kidney injury/et [Etiology] globulin *CD40 antigen/ec [Endogenous Compound] *CD40 ligand/ec [Endogenous Compound] chemokine gamma interferon/ec [Endogenous Compound] *interleukin 12 nephritogenic antigen crescentic glomerulonephritis/et [Etiology] animal cell animal model animal tissue antigen presentation *skin allergy / *etiology adolescent animal cell animal model animal tissue antigen presentation antigen presenting cell article *cellular immunity controlled study cytokine production *delayed hypersensitivity / *etiology effector cell *glomerulonephritis / *etiology immune injury / etiology kidney injury / etiology macrophage macrophage activation male mouse nonhuman priority journal sensitization Th1 cell |
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