Batf Stabilizes the Th17 Cell Developmental Program through Impairment of Stat5-dependent Recruitment of Ets1-Runx1 Complexes

Abstract The emergence of alternative CD4 T cell fates is controlled by transcriptional networks activated downstream of TCR and cytokine signaling inputs. Th17 cells develop from antigen-activated naive CD4 T cells in the presence of IL-6 and TGF-b. An important facet of the Th17 cell program is its intrinsic instability; early development of Th17 cells shares overlapping features with that of Treg cells and Th17 cells are prone to transdifferentiation into Th1-like cells. The basic leucine zipper transcription factor ATF-like (Batf) contributes to the transcriptional programming of multiple effector T cells but is indispensable for Th17 cell development. Although Batf is required for development of Th17 cells, its mechanisms of action to underpin the Th17 program are incompletely understood. Here, we find that in addition to activating core genes of the Th17 program, Batf also acts to restrict expression of genes of the Treg and Th1 programs through its actions to restrain IL-2-induced Stat5 activation, thereby limiting Stat5-dependent recruitment of Ets1-Runx1 factors to Th1 and Treg cell-specific gene loci. Accordingly, Batf acts both to pioneer regulatory elements in Th17-specific genes and limit assembly of a Stat5-Ets1-Runx1 enhanceosome that appears to be required for optimal expression of Th1 and Treg cell-specific genes. Our findings define a new role for Batf in T cell differentiation and unveil an important role for Stat5-Ets1-Runx1 interactions in transcriptional networks that define alternative T cell developmental fates. Supported by NIH R01 DK115172 and T32 AI007051-37