Weiss et al. used CRISPR–Cas9 genome editing to generate an exhaustion-specific PD-1 enhancer-deleted (EnhDel) mouse strain to interrogate its impact on PD-1 expression and CD8+ T cell state. Loss of the enhancer region reduced PD-1 expression in chronic, but not acute, infection, and increased the persistence of EnhDel CD8+ T cells. Enhancer deletion promoted an effector transcriptional state distinct from WT and Pdcd1-KO T cells. EnhDel CD8+ T cells showed enhanced capacity to control chronic viral infection, without causing the excess immunopathology seen with Pdcd1-KO cells.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massach
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) 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. (8) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA. (9) Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (10) 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. (11) 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. (12) 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. (13) 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. (14) 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. (15) 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. (16) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (17) 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. (18) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA. (19) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA. (20) 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. (21) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA. (22) Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (23) 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. (24) 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. (25) 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.
