Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Genentech, South San Francisco, CA, USA.
Nat Immunol. 2024 Aug;25(8):1395-1410. doi: 10.1038/s41590-024-01901-1. Epub 2024 Jul 15.
Interleukin-17 (IL-17)-producing helper T (T17) cells are heterogenous and consist of nonpathogenic T17 (npT17) cells that contribute to tissue homeostasis and pathogenic T17 (pT17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T17 heterogeneity and discover substantial differences in the chromatin landscape of npT17 and pT17 cells both in vitro and in vivo. Compared to other CD4 T cell subsets, npT17 cells share accessible chromatin configurations with regulatory T cells, whereas pT17 cells exhibit features of both npT17 cells and type 1 helper T (T1) 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 T17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npT17 programs and restrains proinflammatory T1-like programs in T17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of T17 heterogeneity as potential targets to mitigate autoimmunity.
白细胞介素 17（IL-17）-产生辅助性 T（T17）细胞是异质的，由有助于组织稳态的非致病性 T17（npT17）细胞和介导组织炎症的致病性 T17（pT17）细胞组成。在这里，我们描述了 T17 异质性的调节途径，并在体外和体内发现了 npT17 和 pT17 细胞染色质景观的显著差异。与其他 CD4 T 细胞亚群相比，npT17 细胞与调节性 T 细胞共享可及染色质构型，而 pT17 细胞则表现出 npT17 细胞和 1 型辅助性 T（T1）细胞的特征。整合转座酶可及染色质测序（scATAC-seq）和单细胞 RNA 测序（scRNA-seq）的单细胞分析，我们推断出控制不同细胞状态的自我强化和相互排斥的调节网络，并预测了调节 T17 细胞致病性的转录因子。我们验证了 BACH2 在体外和体内促进免疫调节性 npT17 程序，并抑制 T17 细胞中的促炎 T1 样程序。此外，人类遗传学表明 BACH2 与多发性硬化症有关。总的来说，我们的工作确定了 T17 异质性的调节因子，作为减轻自身免疫的潜在靶点。
