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.
Highlights
In acute infections, antigen-specific T cells differentiate into activated effector cells and into memory T cells which rapidly gain effector functions and re-expand on subsequent encounter with the same pathogen [1]
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
Summary
Antigen-specific T cells differentiate into activated effector cells and into memory T cells which rapidly gain effector functions and re-expand on subsequent encounter with the same pathogen [1]. During chronic infections, pathogen-specific T cells gradually lose effector functions, fail to expand, and can eventually become physically deleted [2]. These traits are collectively termed T cell exhaustion, and have been described both in animal models of chronic viral infection as well as in human infections with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) [2,3,4]. Expression of PD-1 appears to be a important feature of exhausted CD8+ T cells, as the majority of exhausted cells in mouse models of chronic infection express this receptor, and blockade of the PD-1:PD-L1 axis can restore the function of exhausted CD8+ T cells in humans and mouse models [2,6]. PD-1, for instance, can be expressed by up to 60% of memory CD8+ T cells in healthy individuals, making it challenging to use PD-1 to identify exhausted CD8+ T cells in humans, when the antigen-specificity of potentially exhausted CD8+ T cells is not known [8]
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