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Published ahead of print on January 30, 2008
J Am Soc Nephrol 19: 477-485, 2008
© 2008 American Society of Nephrology
doi: 10.1681/ASN.2007030392
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BASIC RESEARCH

T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis

Richard K. S. Phoon, A. Richard Kitching, Dragana Odobasic, Lynelle K. Jones, Timothy J. Semple and Stephen R. Holdsworth

Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Correspondence: Prof. Stephen R. Holdsworth, Department of Medicine, Monash University, Monash Medical Centre, Level 5 Block E, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: +61 3 9594 5525; Fax: +61 3 9594 6437; E-mail: stephen.holdsworth{at}med.monash.edu.au

Received for publication March 31, 2007. Accepted for publication September 5, 2007.

T-bet is a transcription factor that is essential for T helper (Th)1 lineage commitment and optimal IFN-{gamma} 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.


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