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The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon–producing T helper 17 cells.

Wang, Y;Godec, J;Ben-Aissa, K;Cui, K;Zhao, K;Pucsek, AB;Lee, YK;Weaver, CT;Yagi, R;Lazarevic, V;

T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)--double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN--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 (RORt), respectively, did not generate Th cells with robust IL-17 and IFN- expression. Instead, development of IFN--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--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--producing Th17 cells.