美国麻省理工学院和哈佛大学布罗德研究所Aviv Regev和Vijay K. Kuchroo共同合作，近期取得重要工作进展。他们研究提出BACH2调控T_H17细胞中调节性和促炎性染色质状态的多样化观点。相关研究成果2024年7月15日在线发表于《自然—免疫学》杂志上。

据介绍，白细胞介素-17（IL-17）产生的辅助性T细胞（T_H17）具有异质性，由有助于组织稳态的非致病性T_H17细胞（npT_H17）和介导组织炎症的致病性T_H17细胞（pT_H17）组成。

研究人员表征了T_H17异质性背后的调控途径，并发现npT_H17和pT_H17细胞在体外和体内的染色质格局存在显著差异。与其他CD4⁺ T细胞亚群相比，npT_H17细胞与调节性T细胞具有可接近的染色质结构，而pT_H17细胞同时表现出npT_H17和1型辅助T细胞（T_H1）的特征。

通过整合转座酶可及染色质测序（scATAC-seq）和单细胞RNA测序（scRNA-seq），研究人员推断出控制不同细胞状态的自我强化和互斥的调控网络，并预测了调节T_H17细胞致病性的转录因子。研究人员验证了BACH2在体外和体内促进T_H17细胞中的免疫调节npT_H17程序并抑制促炎T_H1样程序。

此外，人类遗传学表明BACH2与多发性硬化症有关。

总之，这一工作将T_H17异质性的调节因子确定为减轻自身免疫的潜在靶点。

附：英文原文

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

Author: Thakore, Pratiksha I., Schnell, Alexandra, Huang, Linglin, Zhao, Maryann, Hou, Yu, Christian, Elena, Zaghouani, Sarah, Wang, Chao, Singh, Vasundhara, Singaraju, Anvita, Krishnan, Rajesh Kumar, Kozoriz, Deneen, Ma, Sai, Sankar, Venkat, Notarbartolo, Samuele, Buenrostro, Jason D., Sallusto, Federica, Patsopoulos, Nikolaos A., Rozenblatt-Rosen, Orit, Kuchroo, Vijay K., Regev, Aviv

Issue&Volume: 2024-07-15

Abstract: Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover 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 configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) 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 TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.

DOI: 10.1038/s41590-024-01901-1

Source: https://www.nature.com/articles/s41590-024-01901-1