title: Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
abstract: Chronic viral infections are characterized by a state of CD8+T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+T cells. Here we identify a population of virus-specific CD8+T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+T-cell subset was characterized by a unique gene signature that was related to that of CD4+T follicular helper (TFH) cells, CD8+T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+TH1 cells and CD8+terminal effectors. This CD8+T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+T cells. These PD-1+CD8+T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Se Jin
authors: SJ
authors: Im
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Masao
authors: M
authors: Hashimoto
authors: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0421, USA.|Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109, USA.
authors: Michael Y
authors: MY
authors: Gerner
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Junghwa
authors: J
authors: Lee
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Haydn T
authors: HT
authors: Kissick
authors: School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508, Brazil.
authors: Matheus C
authors: MC
authors: Burger
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Qiang
authors: Q
authors: Shan
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: J Scott
authors: JS
authors: Hale
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Judong
authors: J
authors: Lee
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Tahseen H
authors: TH
authors: Nasti
authors: Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors: Arlene H
authors: AH
authors: Sharpe
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Gordon J
authors: GJ
authors: Freeman
authors: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0421, USA.
authors: Ronald N
authors: RN
authors: Germain
authors: School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508, Brazil.
authors: Helder I
authors: HI
authors: Nakaya
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.|Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Hai-Hui
authors: HH
authors: Xue
authors: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Rafi
authors: R
authors: Ahmed
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D007167:Immunotherapy; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor