CD39 Expression Identifies Terminally Exhausted CD8+ T Cells

Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a...

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Vydané v:	PLoS pathogens Ročník 11; číslo 10; s. e1005177
Hlavní autori:	Gupta, Prakash K., Godec, Jernej, Wolski, David, Adland, Emily, Yates, Kathleen, Pauken, Kristen E., Cosgrove, Cormac, Ledderose, Carola, Junger, Wolfgang G., Robson, Simon C., Wherry, E. John, Alter, Galit, Goulder, Philip J. R., Klenerman, Paul, Sharpe, Arlene H., Lauer, Georg M., Haining, W. Nicholas
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 01.10.2015 Public Library of Science (PLoS)
Predmet:	Adenosine Animals Antigens Antigens, CD - immunology Apyrase - immunology Arenaviridae Infections - immunology Biomarkers CD8-Positive T-Lymphocytes - immunology Chromatography, High Pressure Liquid Chronic Disease Disease Models, Animal Flow Cytometry Funding Hepatitis C, Chronic - immunology HIV HIV Infections - immunology Human immunodeficiency virus Humans Infections Laboratory animals Lymphocytes Lymphocytic Choriomeningitis - immunology Lymphocytic choriomeningitis virus - immunology Mice Mice, Inbred C57BL Oligonucleotide Array Sequence Analysis Pathogens Population RNA Virus Infections - immunology T cell receptors T-Lymphocyte Subsets - immunology Transcription factors Viral infections
ISSN:	1553-7374, 1553-7366, 1553-7374
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Abstract	Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
AbstractList	Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. Chronic viral infection induces an acquired state of T cell dysfunction known as exhaustion. Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion. CD39 expression therefore identifies terminal CD8+ T cell exhaustion in mice and humans, and implicates the purinergic pathway in the regulation of exhaustion.
Author	Godec, Jernej Cosgrove, Cormac Robson, Simon C. Goulder, Philip J. R. Junger, Wolfgang G. Sharpe, Arlene H. Wherry, E. John Adland, Emily Lauer, Georg M. Klenerman, Paul Gupta, Prakash K. Wolski, David Alter, Galit Pauken, Kristen E. Haining, W. Nicholas Yates, Kathleen Ledderose, Carola
AuthorAffiliation	6 Ragon Institute of Massachusetts General Hospital, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America 8 Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, United States of America 9 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America 2 Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom Vaccine Research Center, UNITED STATES 10 Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America 4 Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Massachusetts, United States of America 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America 3 Department of Microbiology and Immunobiology and Evergrande Center for Immunologic Disease
AuthorAffiliation_xml	– name: 8 Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, United States of America – name: 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America – name: 2 Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom – name: 9 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America – name: 4 Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Massachusetts, United States of America – name: 3 Department of Microbiology and Immunobiology and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, United States of America – name: 7 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America – name: Vaccine Research Center, UNITED STATES – name: 10 Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America – name: 5 Department of Microbiology and Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, Pennsylvania, United States of America – name: 6 Ragon Institute of Massachusetts General Hospital, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
Author_xml	– sequence: 1 givenname: Prakash K. surname: Gupta fullname: Gupta, Prakash K. – sequence: 2 givenname: Jernej surname: Godec fullname: Godec, Jernej – sequence: 3 givenname: David surname: Wolski fullname: Wolski, David – sequence: 4 givenname: Emily surname: Adland fullname: Adland, Emily – sequence: 5 givenname: Kathleen surname: Yates fullname: Yates, Kathleen – sequence: 6 givenname: Kristen E. surname: Pauken fullname: Pauken, Kristen E. – sequence: 7 givenname: Cormac surname: Cosgrove fullname: Cosgrove, Cormac – sequence: 8 givenname: Carola surname: Ledderose fullname: Ledderose, Carola – sequence: 9 givenname: Wolfgang G. surname: Junger fullname: Junger, Wolfgang G. – sequence: 10 givenname: Simon C. surname: Robson fullname: Robson, Simon C. – sequence: 11 givenname: E. John surname: Wherry fullname: Wherry, E. John – sequence: 12 givenname: Galit surname: Alter fullname: Alter, Galit – sequence: 13 givenname: Philip J. R. surname: Goulder fullname: Goulder, Philip J. R. – sequence: 14 givenname: Paul surname: Klenerman fullname: Klenerman, Paul – sequence: 15 givenname: Arlene H. surname: Sharpe fullname: Sharpe, Arlene H. – sequence: 16 givenname: Georg M. surname: Lauer fullname: Lauer, Georg M. – sequence: 17 givenname: W. Nicholas surname: Haining fullname: Haining, W. Nicholas
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/26485519$$D View this record in MEDLINE/PubMed
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Snippet	Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of... Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers...
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SubjectTerms	Adenosine Animals Antigens Antigens, CD - immunology Apyrase - immunology Arenaviridae Infections - immunology Biomarkers CD8-Positive T-Lymphocytes - immunology Chromatography, High Pressure Liquid Chronic Disease Disease Models, Animal Flow Cytometry Funding Hepatitis C, Chronic - immunology HIV HIV Infections - immunology Human immunodeficiency virus Humans Infections Laboratory animals Lymphocytes Lymphocytic Choriomeningitis - immunology Lymphocytic choriomeningitis virus - immunology Mice Mice, Inbred C57BL Oligonucleotide Array Sequence Analysis Pathogens Population RNA Virus Infections - immunology T cell receptors T-Lymphocyte Subsets - immunology Transcription factors Viral infections
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Title	CD39 Expression Identifies Terminally Exhausted CD8+ T Cells
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