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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Vydané v:	Nature immunology Ročník 25; číslo 10; s. 1871 - 1883
Hlavní autori:	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:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.10.2024 Nature Publishing Group
Predmet:	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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Abstract	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.
AbstractList	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 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 key negative regulator of CD8+ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. While PD-1 blockade can improve viral and tumor control, physiologic 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 novel 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 wildtype and PD-1 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 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 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. 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.
Author	Fung, Megan E. Schwartz, Marc A. Doench, John G. Nguyen, Thao H. Scharer, Christopher D. Sharpe, Arlene H. Martinez, Daniela Bally, Alexander P. R. Chen, Alex C. Y. Neeld, Dennis K. LaFleur, Martin W. Osborn, Jossef F. Nicholas Haining, W. Sen, Debattama R. Boss, Jeremy M. Weiss, Sarah A. Rowe, Jared H. Mei-An Nolan, C. Patterson, Dillon G. Huang, Amy Y. Davidson, Richard A. Sifnugel, Natalia LaSalle, Thomas J. Miller, Brian C. Hegde, Mudra
AuthorAffiliation	1 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA 10 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 16 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 12 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 5 Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA 2 Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 7 Department of Medicine, Harvard Medical School, Boston, MA, USA 8 Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114, USA 9 Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 14 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston
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Copyright	The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
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Notes	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
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PublicationTitle	Nature immunology
PublicationTitleAbbrev	Nat Immunol
PublicationTitleAlternate	Nat Immunol
PublicationYear	2024
Publisher	Nature Publishing Group US Nature Publishing Group
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Snippet	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... 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... 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... 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. While PD-1...
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SubjectTerms	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
Title	Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control
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