BACH2 Enforces 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 immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8(+) T cells diverge from other CD8(+) subsets early after chronic viral infection. However, pathways guarding stem-like CD8(+) T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8(+) T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8(+) T cell differentiation. Single-cell transcriptomics and epigenomics approaches revealed that BACH2 establishes the transcriptional and epigenetic programs of stem-like CD8(+) T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a novel pathway that enforces commitment to stem-like CD8(+) lineage and prevents alternative terminally exhausted cell fate.