T cell responses must be balanced to ensure adequate protection against malignant transformation and an array of pathogens while also limiting damage to healthy cells and preventing autoimmunity. T cell exhaustion serves as a regulatory mechanism to limit the activity and effector function of T cells undergoing chronic antigen stimulation. Exhausted T cells exhibit poor proliferative potential; high inhibitory receptor expression; altered transcriptome, epigenome, and metabolism; and, most importantly, reduced effector function. While exhaustion helps to restrain damage caused by aberrant T cells in settings of autoimmune disease, it also limits the ability of cells to respond against persistent infection and cancer, leading to disease progression. Here we review the process of T cell exhaustion, detailing the key characteristics and drivers as well as highlighting our current understanding of the underlying transcriptional and epigenetic programming. We also discuss how exhaustion can be targeted to enhance T cell functionality in cancer.Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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T细胞耗竭

T 细胞反应必须保持平衡，以确保充分防止恶性转化和一系列病原体，同时限制对健康细胞的损害并预防自身免疫。 T 细胞耗竭是一种调节机制，可限制接受慢性抗原刺激的 T 细胞的活性和效应功能。耗尽的 T 细胞表现出较差的增殖潜力；高抑制性受体表达；转录组、表观基因组和代谢发生改变；最重要的是，效应器功能降低。虽然疲惫有助于抑制异常 T 细胞在自身免疫性疾病中造成的损伤，但它也限制了细胞对抗持续感染和癌症的能力，从而导致疾病进展。在这里，我们回顾了 T 细胞耗竭的过程，详细介绍了关键特征和驱动因素，并强调了我们目前对潜在转录和表观遗传编程的理解。我们还讨论了如何针对疲劳来增强癌症中的 T 细胞功能。《免疫学年度评论》第 42 卷的预计最终在线出版日期为 2024 年 4 月。请参阅 http://www.annualreviews.org/page/journal/发布修订后的估计。