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 transcriptomic and epigenomic approaches revealed that BACH2 established 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 new pathway that enforces commitment to stem-like CD8(+) lineage and prevents an alternative terminally exhausted cell fate. Tuoqi Wu and colleagues show that the transcriptional repressor BACH2 is required early after chronic viral infection to enforce a stem-like fate in activated CD8(+) T cells. BACH2 acts to suppress genes that lead to the exhausted cell state.

Automated summary

The study shows that the transcriptional repressor BACH2 is crucial early after chronic viral infection in influencing CD8(+) T cells, enforcing a stem-like fate and suppressing the formation of exhausted cells.