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

Abstract

Interleukin-17 (IL-17)-producing helper T (T_H17) cells are heterogenous and consist of nonpathogenic T_H17 (npT_H17) cells that contribute to tissue homeostasis and pathogenic T_H17 (pT_H17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T_H17 heterogeneity and discover substantial differences in the chromatin landscape of npT_H17 and pT_H17 cells both in vitro and in vivo. Compared to other CD4⁺ T cell subsets, npT_H17 cells share accessible chromatin configurations with regulatory T cells, whereas pT_H17 cells exhibit features of both npT_H17 cells and type 1 helper T (T_H1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating T_H17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npT_H17 programs and restrains proinflammatory T_H1-like programs in T_H17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of T_H17 heterogeneity as potential targets to mitigate autoimmunity.