T-bet and Runx transcription factors are required for the ontogeny of pathogenic IFNγ-producing Th17 cells (LYM3P.729)

Abstract

Abstract Functional plasticity of CD4+ Th cells can be advantageous for the host as it creates diversity that is required to establish a productive immune response against a variety of pathogenic microbes. However, the acquisition of a gene expression profile associated with the opposing CD4+ Th lineages can lead to increased susceptibility to autoimmune diseases. For example, Th17 cells can give rise to IL-17A/IFNγ-double producing cells, which have been implicated in the development of autoimmune diseases. However, our understanding of the molecular mechanisms that govern the generation of IFNγ-producing Th17 cells during an inflammatory response remains incomplete. Here we report that, contrary to current concepts, co-expression of Th1- and Th17-cell master transcription factors, T-bet and RORγt, respectively, did not generate Th cells with strong dual Th1 and Th17 features. Instead, the development of Th1-like Th17 cells required T-bet and Runx1 or Runx3. Indeed, interleukin (IL)-12 stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet dependent manner. Conversely, T-bet or Runx1 deficiency, or inhibition of Runx transcriptional activity, impaired the development of Th1-like Th17 cells during experimental autoimmune encephalomyelitis in vivo. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFNγ-producing Th17 cells.