‘T cell exhaustion’ is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection. Their responses highlight the dichotomy between terminally differentiated exhausted T cells that are TCF1^– and the self-renewing TCF1⁺ population from which they derive. These TCF1⁺ cells are considered by some to have stem cell-like properties akin to memory T cell populations, but the developmental relationships are unclear at present. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of exhaustion, but key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations.

“ T细胞衰竭”是一个宽泛的术语，已被用来描述T细胞对慢性抗原刺激的反应，首先是在慢性病毒感染的情况下，但最近是在对肿瘤的反应中。了解精疲力竭的特征和途径对检查站封锁和过继性T细胞转移疗法的成功具有至关重要的意义。在此观点文章中，该领域的18位专家告诉我们，精疲力竭对他们意味着什么，从完全缺乏效应子功能到改变功能以预防免疫病理学，以及癌症和慢性感染之间的潜在差异。他们的反应突显出终末分化的疲乏T细胞TCF1 ^–与自我更新的TCF1 ⁺之间的二分法他们从中获得的人口。有人认为这些TCF1 ⁺细胞具有类似于记忆T细胞群体的干细胞样特性，但目前发展关系尚不清楚。最近的研究还强调了转录调节因子TOX在驱动表观遗传穷竭中的重要作用，但关键问题仍然在于逆转表观遗传衰老程序的潜力以及这可能如何影响T细胞群体的持久性。