T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis
Open Access
- 1 March 2008
- journal article
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 19 (3) , 477-485
- https://doi.org/10.1681/asn.2007030392
Abstract
T-bet is a transcription factor that is essential for T helper (Th)1 lineage commitment and optimal IFN-γ production by CD4+ T cells. We examined the role of T-bet in the development of experimental crescentic glomerulonephritis, which is induced by Th1-predominant, delayed-type hypersensitivity-like responses directed against a nephritogenic antigen. Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in T-bet−/− and wild-type C57BL/6 mice. Compared with wild-type controls, renal injury was attenuated in T-bet−/− mice with glomerulonephritis, evidenced by less proteinuria, glomerular crescents, and tubulointerstitial inflammation. Accumulation of glomerular CD4+ T cells and macrophages was decreased, and was associated with reduced intrarenal expression of the potent Th1 chemoattractants CCL5/RANTES and CXCL9/Mig. Supporting the pro-inflammatory nature of T-bet signaling, assessment of systemic immunity confirmed that T-bet−/− mice had a reduction in Th1 immunity. The kinetic profile of T-bet mRNA in wild-type mice supported the hypothesis that T-bet deficiency attenuates renal injury in part by shifting the Th1/Th2 balance away from a Th1 phenotype. Expression of renal and splenic IL-17A, characteristically expressed by the Th17 subset of effector T cells, which have been implicated in the pathogenesis of autoimmune disease, was increased in T-bet−/− mice. We conclude that T-bet directs Th1 responses that induce renal injury in experimental crescentic glomerulonephritis.Keywords
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