Journal
CELL REPORTS
Volume 23, Issue 8, Pages 2318-2329Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.04.088
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Funding
- NIH
- SENSHIN Medical Research Foundation
- Institutional Program for Young Researcher Overseas Visits by Keio University
- Japan Society for the Promotion of Science
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI050761] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR050772] Funding Source: NIH RePORTER
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T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor ROR gamma t, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-beta/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il 17a and Mil loci in a ROR gamma t-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for ROR gamma t-dependent gene expression in Th17 cell-driven autoimmune diseases.
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