T-bet deficiency attenuates renal injury in experimental crescentic glomerulonephritis.
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.
Phoon
Richard K S
RK
Department of Medicine, Monash University, Monash Medical Centre, Level 5 Block E, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Kitching
A Richard
AR
Odobasic
Dragana
D
Jones
Lynelle K
LK
Semple
Timothy J
TJ
Holdsworth
Stephen R
SR
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism / Q000502:physiology*; D000098815:T-bet Transcription Factor
D018941:Antigens, CD19; D016207:Cytokines; D020381:Interleukin-17; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor