Received March 31, 2007
Accepted on September 5, 2007

BASIC RESEARCH

T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis

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

¹ To whom correspondence should be addressed. E-mail: stephen.holdsworth{at}med.monash.edu.au.

	Abstract

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