Hyperactivation of CD8 T cells precedes exhaustion following viral infection (45.9)

Abstract

Abstract Developing an in-depth understanding of the factors that regulate the induction, quality, and longevity of T cell responses is essential for devising rational strategies to promote anti-pathogen immunity. Cellular immune responses to many persistent viral infections are associated with the development of T cell exhaustion, which is characterized by the inability to produce anti-viral cytokines and proliferate. We have used IFN-γ-Thy1.1 cytokine reporter mice to dissect the initial activation events and functional traits of CD8 T cells as they respond following acute or persistent lymphocytic choriomeningitis virus (LCMV) infections. We show that a positive correlation exists between the expression of the Thy1.1 reporter molecule and IFN-γ production. Significantly, we show that expression of the Thy1.1 IFN-γ reporter molecule is elevated during the early stages of infections associated with the subsequent development of T cell exhaustion but is not as markedly upregulated following infections that become well controlled. This parallels the expression of PD-1, which is known to be upregulated on exhausted cells. Collectively, these data indicate that exhausted T cells, which are ineffective at eradicating persisting antigens, are derived from populations of cells that are initially hyperactivated. Thus, the blockade of this hyperactivation may represent a novel therapeutic approach to enhance cellular immunity against intracellular pathogens.