CD39 Expression Identifies Terminally Exhausted CD8+ T Cells

• DOI: 10.1371/journal.ppat.1005177
• Publication Date: 2015-10-20T18:28:18Z
• Authors: Prakash K. Gupta; Jernej Godec; David Wolski; Emily Adland; Kathleen Yates; Kristen E. Pauken; Cormac Cosgrove; Carola Ledderose; Wolfgang G. Junger; Simon C. Robson; E. John Wherry; Galit Alter; Philip J. R. Goulder; Paul Klenerman; Arlene H. Sharpe; Georg M. Lauer; W. Nicholas Haining
• Keywords: 0301 basic medicine; 570; QH301-705.5; 610; HIV Infections; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Mice; 03 medical and health sciences; RNA Virus Infections; Antigens, CD; T-Lymphocyte Subsets; Animals; Arenaviridae Infections; Humans; Lymphocytic choriomeningitis virus; Biology (General); Chromatography, High Pressure Liquid; Oligonucleotide Array Sequence Analysis; Apyrase; RC581-607; Hepatitis C, Chronic; Flow Cytometry; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Chronic Disease; Immunologic diseases. Allergy; Biomarkers; Research Article

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.