The Th17-Defining Transcription Factor ROR{gamma}t Promotes Glomerulonephritis.

TY - JOUR

T1 - The Th17-Defining Transcription Factor ROR{gamma}t Promotes Glomerulonephritis.

AU - Steinmetz, Oliver

AU - Summers, Shaun A

AU - Gan, Poh-Yi

AU - Semple, Timothy

AU - Holdsworth, Stephen R

AU - Kitching, A Richard

PY - 2011

Y1 - 2011

N2 - Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, ROR t, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and ROR t-deficient (ROR t(-/-)) mice. ROR t(-/-) mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because ROR 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 naïve wild-type or ROR t(-/-) mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving ROR t(-/-) cells were protected. To determine the effect of ROR t deficiency specifically in T helper cells, we isolated naïve CD4(+) T cells from wild-type and ROR t(-/-) mice and transferred them into Rag1(-/-) animals. Recipients of wild-type CD4(+) T cells developed severe glomerulonephritis whereas recipients of ROR t(-/-) cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by ROR t deficiency, we transferred naïve CD4(+) T cells depleted of Tregs into Rag1(-/-) mice. Recipients of wild-type, Treg-depleted, CD4(+) T cells developed severe glomerulonephritis whereas recipients of ROR t(-/-), Treg-depleted CD4(+) T cells did not. Taken together, this study demonstrates that ROR t promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses.

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

M3 - SCORING: Zeitschriftenaufsatz

VL - 22

SP - 472

EP - 483

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 3

M1 - 3

ER -