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.