The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection
Kristen E. Pauken,
Jernej Godec,
Pamela M. Odorizzi,
Keturah E. Brown,
Kathleen B. Yates,
Shin Foong Ngiow,
Kelly P. Burke,
Seth Maleri,
Shannon M. Grande,
Loise M. Francisco,
Mohammed-Alkhatim Ali,
Sabrina Imam,
Gordon J. Freeman,
W. Nicholas Haining,
E. John Wherry,
Arlene H. Sharpe
Affiliations
Kristen E. Pauken
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Jernej Godec
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Pamela M. Odorizzi
Institute for Immunology and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Keturah E. Brown
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Kathleen B. Yates
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Shin Foong Ngiow
Institute for Immunology and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Kelly P. Burke
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
Seth Maleri
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Shannon M. Grande
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Loise M. Francisco
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Mohammed-Alkhatim Ali
Institute for Immunology and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Sabrina Imam
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Gordon J. Freeman
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
W. Nicholas Haining
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Hematology/Oncology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
E. John Wherry
Institute for Immunology and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author
Arlene H. Sharpe
Department of Immunology, Blavatnik Institute, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA; Corresponding author
Summary: The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.
