Prevention of CD8 T Cell Deletion during Chronic Viral Infection.

David G Brooks,Michael B A Oldstone,Antoinette Tishon,Dorian B Mcgavern

doi:10.3390/v13071189

Abstract

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.

Highlights

At the beginning of what will become a chronic infection, heightened and sustained antigenic signaling and inflammatory factors enhance the expression of immunosuppressive cytokines and multiple inhibitory receptors/ligands (e.g., IL10, PD1, PDL1) that program and maintain T cell exhaustion and viral persistence [1,2,3,4]
The exhaustion of antiviral T cell function is observed during many chronic viral infections, including HIV
We demonstrate that distinct from CD8 T cell functional exhaustion, the physical deletion of high-affinity lymphocytic choriomeningitis virus (LCMV)-NP396–404 specific CD8 T cells in chronic LCMV infection is due to increased virus infection and the loss of costimulatory signals

Summary

Introduction

At the beginning of what will become a chronic infection, heightened and sustained antigenic signaling and inflammatory factors enhance the expression of immunosuppressive cytokines and multiple inhibitory receptors/ligands (e.g., IL10, PD1, PDL1) that program and maintain T cell exhaustion and viral persistence [1,2,3,4]. The exhaustion of antiviral T cell function is observed during many chronic viral infections, including HIV and hepatitis B and C virus (HBV, HCV) infections of humans, lymphocytic choriomeningitis virus (LCMV) infection of rodents, and in response to many cancers [3], suggesting that shared mechanisms triggered by increased and/or sustained antigen regulate T cell inactivation. Understanding the mechanisms governing T cell exhaustion and deletion is important if we intend to eradicate persistent viral infections

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Conclusion