Chronic antigen stimulation during viral infections and cancer can lead to T cell exhaustion, which is characterized by reduced effector function and proliferation, and the expression of inhibitory immune checkpoint receptors. Recent studies have demonstrated that T cell exhaustion results in wholescale epigenetic remodeling that confers phenotypic stability to these cells and prevents T cell reinvigoration by checkpoint blockade. Here, we review foundational technologies to profile the epigenome at multiple scales, including mapping the locations of transcription factors and histone modifications, DNA methylation and three-dimensional genome conformation. We discuss how these technologies have elucidated the development and epigenetic regulation of exhausted T cells and functional implications across viral infection, cancer, autoimmunity and engineered T cell therapies. Finally, we cover emerging multi-omic and genome engineering technologies, current and upcoming opportunities to apply these to T cell exhaustion, and therapeutic opportunities for T cell engineering in the clinic.

病毒感染和癌症期间的慢性抗原刺激可导致 T 细胞耗竭，其特点是效应器功能和增殖以及抑制性免疫检查点受体表达降低。最近的研究表明，T 细胞耗竭会导致整体表观遗传重塑，从而赋予这些细胞表型稳定性，并通过检查点封锁阻止 T 细胞重新焕发活力。在这里，我们回顾了在多个尺度上分析表观基因组的基础技术，包括绘制转录因子和组蛋白修饰的位置、DNA 甲基化和三维基因组构象。我们讨论这些技术如何阐明耗竭 T 细胞的发育和表观遗传调控，以及对病毒感染、癌症、自身免疫和工程 T 细胞疗法的功能影响。最后，我们介绍了新兴的多组学和基因组工程技术、当前和即将到来的将这些技术应用于 T 细胞耗竭的机会，以及 T 细胞工程在临床中的治疗机会。