期刊
NATURE IMMUNOLOGY
卷 22, 期 3, 页码 370-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-021-00868-7
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资金
- NIH [AI105343, AI117950, AI082630, AI112521, AI115712, AI108545, CA210944, AG056524, CA234842]
- NIAMS
- NIAID
- NHGRI
- NINDS
- National Cancer Institute
- NIDDK
- NIH Office of Dietary Supplements Research Scholar scholarship
- Stand Up To Cancer
- Parker Institute for Cancer Immunotherapy
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.
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.
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