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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Veröffentlicht in:Nature immunology Jg. 25; H. 10; S. 1871 - 1883
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.10.2024
Nature Publishing Group
Schlagworte:
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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Zusammenfassung: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.
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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