Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control

PD-1 is a key negative regulator of CD8 + T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechan...

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Vydáno v:	Nature immunology Ročník 25; číslo 10; s. 1871 - 1883
Hlavní autoři:	Weiss, Sarah A., Huang, Amy Y., Fung, Megan E., Martinez, Daniela, Chen, Alex C. Y., LaSalle, Thomas J., Miller, Brian C., Scharer, Christopher D., Hegde, Mudra, Nguyen, Thao H., Rowe, Jared H., Osborn, Jossef F., Patterson, Dillon G., Sifnugel, Natalia, Mei-An Nolan, C., Davidson, Richard A., Schwartz, Marc A., Bally, Alexander P. R., Neeld, Dennis K., LaFleur, Martin W., Boss, Jeremy M., Doench, John G., Nicholas Haining, W., Sharpe, Arlene H., Sen, Debattama R.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.10.2024 Nature Publishing Group
Témata:	631/250/1619/554/1834 631/250/2502/2170 631/250/255/2514 631/337/100/102 Animals Biomedical and Life Sciences Biomedicine CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell activation Chronic infection Clonal deletion Enhancer Elements, Genetic - genetics Epigenesis, Genetic Epigenetics Immunological memory Immunology Infections Infectious Diseases Lymphocyte Activation - immunology Lymphocytes Lymphocytes T Lymphocytic Choriomeningitis - immunology Lymphocytic Choriomeningitis - virology Memory cells Mice Mice, Inbred C57BL Mice, Knockout PD-1 protein Programmed Cell Death 1 Receptor - genetics Programmed Cell Death 1 Receptor - metabolism Viral infections
ISSN:	1529-2908, 1529-2916, 1529-2916
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Popis
Shrnutí:	PD-1 is a key negative regulator of CD8 + T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8 + T cells in chronic infection, creating a ‘sweet spot’ of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1 -knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8 + T cell dysfunction while avoiding excess immunopathology. PD-1 is a critical modulator of CD8 + T cell activation and exhaustion. Sen and colleagues show that a cell-state-specific enhancer tunes PD-1 expression exclusively in exhaustion and that deletion of this enhancer improves CD8 + T cell function.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 S.A.W., D.R.S., W.N.H. and A.H.S. conceived the study and designed the experiments. S.A.W., A.Y.H., M.E.F., D.M., A.C.Y.C., T.J.L., B.C.M., M.H., T.H.N., J.H.R., N.S., C.M.N., D.G.P., J.F.O., and R.A.D. performed experiments and/or data analysis. A.P.R.B., D.K.N, C.D.S., and J.M.B. provided ATAC-seq data. S.A.W., D.R.S. and A.H.S. wrote the manuscript. M.A.S., M.W.L., J.G.D., and W.N.H. contributed key discussions. All authors reviewed and edited the manuscript. Author Contribution Statement
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-024-01961-3