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.