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 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.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
Prakash K
PK
Gupta
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; 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.
Jernej
J
Godec
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Massachusetts, United States of America.
David
D
Wolski
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
Emily
E
Adland
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Kathleen
K
Yates
Department of Microbiology and Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, Pennsylvania, United States of America.
Kristen E
KE
Pauken
Ragon Institute of Massachusetts General Hospital, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Cormac
C
Cosgrove
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Carola
C
Ledderose
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Wolfgang G
WG
Junger
Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, United States of America.
Simon C
SC
Robson
Department of Microbiology and Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, Pennsylvania, United States of America.
E John
EJ
Wherry
Ragon Institute of Massachusetts General Hospital, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Galit
G
Alter
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
Philip J R
PJ
Goulder
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
Paul
P
Klenerman
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; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
Arlene H
AH
Sharpe
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Massachusetts, United States of America.
Georg M
GM
Lauer
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
W Nicholas
WN
Haining
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001081:Apyrase / Q000276:immunology*; D001117:Arenaviridae Infections / Q000276:immunology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D012327:RNA Virus Infections / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D015703:Antigens, CD; D015415:Biomarkers; D001081:Apyrase; C067869:CD39 antigen