The Th17-defining transcription factor RORgammat promotes glomerulonephritis

Oliver Steinmetz, Shaun Andrew Summers, Poh-Yi Gan, Timothy Semple, Stephen Holdsworth, Arthur Kitching

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58 Citations (Scopus)

Abstract

Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, RORI?t, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and RORI?t-deficient (RORI?t(-/-)) mice. RORI?t(-/-) mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because RORI?t(-/-) mice lack lymph nodes, which may influence the development of nephritis, we performed cell-transfer studies. We reconstituted Rag1(-/-) mice, which lack adaptive immunity but otherwise have normal architecture of the lymphatic system, with splenocytes from na??ve wild-type or RORI?t(-/-) mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving RORI?t(-/-) cells were protected. To determine the effect of RORI?t deficiency specifically in T helper cells, we isolated na??ve CD4(+) T cells from wild-type and RORI?t(-/-) mice and transferred them into Rag1(-/-) animals. Recipients of wild-type CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORI?t(-/-) cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by RORI?t deficiency, we transferred na??ve CD4(+) T cells depleted of Tregs into Rag1(-/-) mice. Recipients of wild-type, Treg-depleted, CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORI?t(-/-), Treg-depleted CD4(+) T cells did not. Taken together, this study demonstrates that RORI?t promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses.
Original languageEnglish
Pages (from-to)472 - 483
Number of pages12
JournalJournal of the American Society of Nephrology
Volume22
Issue number3
DOIs
Publication statusPublished - 2011

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