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

Autor:	Weiss SA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA., Huang AY; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA., Fung ME; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Martinez D; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA., Chen ACY; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA., LaSalle TJ; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA., Miller BC; Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Scharer CD; Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA., Hegde M; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Nguyen TH; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Rowe JH; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Osborn JF; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Patterson DG; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Sifnugel N; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Mei-An Nolan C; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Davidson RA; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Schwartz MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Bally APR; Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA., Neeld DK; Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA., LaFleur MW; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Boss JM; Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA., Doench JG; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Nicholas Haining W; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; ArsenalBio, San Francisco, CA, USA., Sharpe AH; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. arlene_sharpe@hms.harvard.edu.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. arlene_sharpe@hms.harvard.edu., Sen DR; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. dsen@mgh.harvard.edu.; Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. dsen@mgh.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, MA, USA. dsen@mgh.harvard.edu.; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. dsen@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature immunology [Nat Immunol] 2024 Oct; Vol. 25 (10), pp. 1871-1883. Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1038/s41590-024-01961-3
Abstrakt:	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. (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
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