Journal
IMMUNITY
Volume 40, Issue 3, Pages 355-366Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2014.01.002
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Funding
- Intramural NIH HHS [ZIA BC011431-02] Funding Source: Medline
- NCI NIH HHS [P30 CA013148] Funding Source: Medline
- NIAMS NIH HHS [P30 AR048311] Funding Source: Medline
- NIDDK NIH HHS [P01 DK071176] Funding Source: Medline
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T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-gamma-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-gamma-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (ROR gamma t), respectively, did not generate Th cells with robust IL-17 and IFN-gamma expression. Instead, development of IFN-gamma-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-gamma-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-gamma-producing Th17 cells.
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