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.
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We thank S. Knemeyer at SciStories for illustrations. This work was supported by the National Institutes of Health awards K08CA230188, U01CA260852 and UM1HG012076, the Parker Institute for Cancer Immunotherapy, a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a Cancer Research Institute Technology Impact Award, a Baxter Foundation Faculty Scholar Award, and a Pew-Stewart Scholars for Cancer Research Award. J.A.B. was supported by a Stanford Graduate Fellowship and a National Science Foundation Graduate Research Fellowship under grant no. DGE-1656518.
A.T.S. is a scientific founder of Immunai and founder of Cartography Biosciences and receives research funding from Merck Research Laboratories and Allogene Therapeutics. J.A.B and B.D. declare no competing interests.
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Belk, J.A., Daniel, B. & Satpathy, A.T. Epigenetic regulation of T cell exhaustion. Nat Immunol 23, 848–860 (2022). https://doi.org/10.1038/s41590-022-01224-z