Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nat Immunol. 2021 Mar;22(3):370-380. doi: 10.1038/s41590-021-00868-7. Epub 2021 Feb 11.
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.
在慢性感染和癌症中，自我更新的 CD8 T 细胞亚群维持长期免疫，对免疫疗法的效果至关重要。这些类似于干细胞的 CD8 T 细胞在慢性病毒感染后早期与其他 CD8 亚群分化。然而，保护类似于干细胞的 CD8 T 细胞免受终末衰竭的途径仍不清楚。在这里，我们表明，编码转录抑制因子 BACH2 的基因在类似于干细胞的 CD8 T 细胞中转录和表观遗传上是活跃的，但在感染后早期的终末衰竭细胞中则不然。BACH2 的过表达强制了类似于干细胞的细胞命运，而 BACH2 的缺乏则损害了类似于干细胞的 CD8 T 细胞分化。单细胞转录组学和表观基因组学方法揭示了 BACH2 建立了类似于干细胞的 CD8 T 细胞的转录和表观遗传程序。此外，BACH2 通过转录抑制和表观遗传沉默抑制了驱动终末衰竭的分子程序。因此，我们的研究揭示了一个新的途径，该途径强制类似于干细胞的 CD8 谱系的承诺，并防止替代的终末衰竭细胞命运。
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