BACH2 Establishes the Transcriptional and Epigenetic Programs of Stem-Like CD8 T cells

During chronic infection and cancer, a self-renewing CD8 T cell subset maintains long-term T-cell immunity and mediate the response induced by immunotherapy. These stem-like CD8 T cells diverge from other CD8 subsets early in the immune response and display distinct transcriptional and epigenetic signatures. Here, we show that locus encoding transcriptional factor BACH2 is transcriptionally and epigenetically active in stem-like CD8 T cells but not in terminally exhausted CD8 T cells. Overexpression of BACH2 enforces the stem-like cell fate, whereas Bach2 deficiency impairs stem-like CD8 T cell differentiation. Using single-cell transcriptomics and epigenomics approaches, we demonstrate BACH2 as a key regulator of the transcriptional and epigenetic programs of stem-like CD8 T cells. In addition, BACH2 suppresses genes and pathways that drive terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a novel pathway responsible for establishing the unique transcriptional and epigenetic program of stem-like CD8 T cells. Overall design: ATAC-Seq analysis of stem-like and terminally exhausted antigen-specific CD8 T cells after chronic viral infection. Single-cell RNA-Seq, RNA-Seq, and ATAC-Seq analysis of control, BACH2 over expression, and BACH2 deficient antigen specific CD8 T cells after chronic viral infection.

在慢性感染与癌症状态下，一类自我更新型CD8 T细胞亚群可维持长期T细胞免疫，并介导免疫治疗诱导的免疫应答。此类干细胞样CD8 T细胞（stem-like CD8 T cells）可在免疫应答早期即与其他CD8 T细胞亚群产生分化，并展现出独特的转录组与表观基因组特征。本研究发现，编码转录因子BACH2的基因座在干细胞样CD8 T细胞中呈现转录与表观遗传层面的激活状态，而在终末耗竭型CD8 T细胞中则无此激活特征。过表达BACH2可强化干细胞样细胞的命运倾向，而Bach2基因缺失则会阻碍干细胞样CD8 T细胞的分化过程。本研究借助单细胞转录组学与表观基因组学技术，证实BACH2是调控干细胞样CD8 T细胞转录与表观遗传程序的关键调控因子。此外，BACH2可通过转录抑制与表观遗传沉默机制，抑制介导终末耗竭的相关基因与信号通路。综上，本研究揭示了一条调控干细胞样CD8 T细胞独特转录与表观遗传程序的全新通路。实验整体设计：对慢性病毒感染后分离的干细胞样CD8 T细胞与终末耗竭型抗原特异性CD8 T细胞（antigen-specific CD8 T cells）进行ATAC-Seq分析；对慢性病毒感染后分离的对照组、BACH2过表达组及BACH2基因缺失组的抗原特异性CD8 T细胞分别开展单细胞RNA-Seq、RNA-Seq及ATAC-Seq分析。