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Review
. 2022 Jun;23(6):848-860.
doi: 10.1038/s41590-022-01224-z. Epub 2022 May 27.

Epigenetic regulation of T cell exhaustion

Julia A Belk #  1   2 , Bence Daniel #  2   3 , Ansuman T Satpathy  4   5   6   7
Affiliations
Review

Epigenetic regulation of T cell exhaustion

Julia A Belk et al. Nat Immunol. 2022 Jun.

Abstract

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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Conflict of interest statement

Competing interests

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.

Figures

Fig. 1 |
Fig. 1 |. Epigenetic regulation of gene expression.
a, Promoters, enhancers and insulators are shown in their active and repressed states. b, Technologies to map protein localization on chromatin (ChIP–seq), accessible chromatin (ATAC–seq) and DnA methylation (bisulfite-seq). c, Technologies to map spatial genome architecture. eRnA, enhancer RnA; GTF, general transcription factor; MBD, methyl-CpG binding domain; P-TeFb, positive transcription elongation factor.
Fig. 2 |
Fig. 2 |. CD8+ T cell development and key mediators of T cell exhaustion.
a, Differentiation trajectory of CD8+ T cells. Important surface markers and TFs are indicated on each cell type. b, Key transcriptional regulators of CD8+ T cells and exhausted CD8+ T cells. IFn-γ, interferon gamma; TnF, tumor necrosis factor.
Fig. 3 |
Fig. 3 |. Emerging technologies for studying the epigenome.
a, CRISPR–Cas9-based technologies for perturbing the epigenome. b, Multi-omic technologies for cell profiling. HDR, homology-directed repair; nHeJ, nonhomologous end joining.
Fig. 4 |
Fig. 4 |. Opportunities for epigenetic engineering in the clinic.
a, Engineered T cell therapies. b, Emerging strategies for genetic and epigenetic engineering.
See this image and copyright information in PMC

References

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