title: Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.
abstract: Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.
authors.affiliation: Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Odorizzi
authors.affiliation: Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.affiliation: Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Paley
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 Broad Institute of MIT and Harvard, Cambridge, MA 02142 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Arlene
authors.initials: A
authors.lastname: Sharpe
authors.affiliation: Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 Department of Microbiology and Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 wherry@mail.med.upenn.edu.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001973:Bromodeoxyuridine; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000502:physiology; D005434:Flow Cytometry; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000378:metabolism*
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D001973:Bromodeoxyuridine