BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells

Abstract

Th17 cells are heterogenous, consisting of non-pathogenic Th17 cells (npTh17) that contribute to tissue homeostasis and pathogenic Th17 cells (pTh17) that mediate tissue inflammation. Here, we characterized regulatory pathways underlying Th17 heterogeneity and discovered substantial differences in the chromatin landscape of npTh17 and pTh17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTh17 cells share accessible chromatin programs with Tregs, whereas pTh17 cells exhibit features of both npTh17 cells and Th1 cells. Integrating single-cell ATAC-seq and single-cell RNA-seq, we inferred self-reinforcing and mutually exclusive regulatory networks controlling the different cell states and predicted transcription factors (TFs) regulating Th17 cell pathogenicity. We validated that BACH2 promotes immunomodulatory npTh17 programs and restrains pro-inflammatory Th1-like programs in Th17 cells in vitro and in vivo, Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identified regulators of Th17 heterogeneity as potential targets to mitigate autoimmunity.