TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
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DOI：
10.1038/s41586-019-1325-x
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发表时间：
2019-07-11
期刊：
影响因子：
64.8
通讯作者：
Wherry, E. John
中科院分区：
文献类型：
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作者：
Khan, Omar;Giles, Josephine R.;Wherry, E. John
与效应性（T-eff）或记忆性（T-mem）CD8(+) T细胞相比，慢性感染和癌症中的耗竭性CD8(+) T（T-ex）细胞效应功能有限，抑制性受体共表达水平高，且转录变化广泛。T - ex细胞是免疫检查点阻断和其他免疫疗法的重要临床靶点。从表观遗传学角度来看，T - ex细胞是一个独特的免疫亚群，与T - eff和T - mem细胞相比具有独特的染色质景观。然而，调控T - ex细胞转录和表观遗传发育的机制仍然未知。在此我们确定高迁移率族蛋白盒转录因子TOX是小鼠T - ex细胞的核心调节因子。TOX对T - eff和T - mem细胞的形成基本是可有可无的，但对耗竭至关重要：在没有TOX的情况下，T - ex细胞无法形成。TOX由钙调神经磷酸酶和NFAT2诱导，并在前馈环路中发挥作用，在此环路中它在T - ex细胞中变得不依赖钙调神经磷酸酶并持续存在。因此，TOX的强烈表达通过将持续性刺激转化为独特的T - ex细胞转录和表观遗传发育程序，从而导致细胞定向分化为T - ex细胞。
Exhausted CD8(+) T (T-ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T-eff) or memory (T-mem) CD8(+) T cells. T-ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T-ex cells are a distinct immune subset, with a unique chromatin landscape compared with T-eff and T-mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T-ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T-ex cells in mice. TOX is largely dispensable for the formation of T-eff and T-mem cells, but it is critical for exhaustion: in the absence of TOX, T-ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T-ex cells. Robust expression of TOX therefore results in commitment to T-ex cells by translating persistent stimulation into a distinct T-ex cell transcriptional and epigenetic developmental program.