The Th17-Defining Transcription Factor ROR (cid:1) t Promotes Glomerulonephritis

Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, ROR (cid:1) t, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and ROR (cid:1) t-deficient (ROR (cid:1) t (cid:1) / (cid:1) ) mice. ROR (cid:1) t (cid:1) / (cid:1) mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because ROR (cid:1) t / (cid:1) mice lack lymph nodes, which may influence the development of nephritis, we performed cell-transfer studies. We reconstituted Rag1 (cid:1) / (cid:1) mice, which lack adaptive immunity but otherwise have normal architecture of the lym-phatic system, with splenocytes from naïve wild-type or ROR (cid:1) t (cid:1) / (cid:1) mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving ROR (cid:1) t (cid:1) / (cid:1) cells were protected. To determine the effect of ROR (cid:1) t deficiency specifically in T helper cells, we isolated naïve CD4 (cid:2) T cells from wild-type and ROR (cid:1) t (cid:1) / (cid:1) mice and transferred them into Rag1 (cid:1) / (cid:1) animals. Recipients of wild-type CD4 (cid:2) T cells developed severe glomerulonephritis whereas recipients of ROR (cid:1) t (cid:1) / (cid:1) cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by ROR (cid:1) t deficiency, we transferred naïve CD4 (cid:2) T cells depleted of Tregs into Rag1 (cid:1) / (cid:1) mice. Recipients of wild-type, Treg-depleted, CD4 (cid:2) T cells developed severe glomerulonephritis whereas recipients of ROR (cid:1) t (cid:1) / (cid:1) , Treg-depleted CD4 (cid:2) T cells did not. Taken together, this study demonstrates that ROR (cid:1) t promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses.

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