CD39 Expression Identifies Terminally Exhausted CD8+ T Cells

PLoS Pathog. 2015 Oct 20;11(10):e1005177. doi: 10.1371/journal.ppat.1005177. eCollection 2015 Oct.


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.

MeSH terms

  • Animals
  • 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
  • HIV Infections / immunology
  • Hepatitis C, Chronic / immunology
  • Humans
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • RNA Virus Infections / immunology*
  • T-Lymphocyte Subsets / immunology*


  • Antigens, CD
  • Biomarkers
  • Apyrase
  • CD39 antigen