Regulation of CD8 T Cells during Chronic Viral Infection Open Access

West, Erin Elizabeth (2011)

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Regulation of CD8 T Cells during Chronic Viral Infection

CD8 T cells play an important role in controlling viral infections, however in the case of chronic infections, where antigen persists, CD8 T cells become dysfunctional. There has been much emphasis in understanding the difference in CD8 T cell responses during acute and chronic infection to better design vaccines and therapeutic strategies for chronic infections, although important questions remain.

First, a critical aspect of designing a T cell based vaccine for chronic diseases is understanding memory CD8 T cell responses to persistent antigen re-stimulation. Although, naïve and memory CD8 T cell responses have been well defined during rapidly cleared infections, less is known about memory responses during antigen persistence. To address this, we compared the responses of memory and naïve CD8 T cells to acute and chronic lymphocytic virus infection (LCMV). Memory cells dominated over naïve cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, memory cells were rapidly lost when infection was not quickly reduced, unlike naïve cells. This loss of memory CD8 T cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4 T cell help.

Secondly, we show that IL-2 therapy can act directly on exhausted CD8 T cells during chronic viral infection, increasing their numbers and function, while converting their phenotype towards one associated with decreased exhaustion, including decreased expression of multiple inhibitory receptors, increased expression of CD44 and T-bet, and upregulation of IL-7Rα (CD127), a marker of functional memory cells. Surprisingly, these enhancing effects of IL-2 therapy were not correlated with significantly decreased viral loads. However, combining IL-2 therapy with blockade of the inhibitory PD-1 pathway had striking synergistic effects, resulting in both enhanced T cell responses and decreased viral load.

Overall, these studies emphasize the importance of designing vaccines that elicit effective CD4 T cell help and rapidly control infection, and indicate that combined IL-2 therapy and PD-1 blockade may be a useful regimen for treating human chronic infections and cancer.

Table of Contents

Table of Contents

Table of Contents
List of Figures/Tables

Chapter 1: Introduction

LCMV as a Model System for Studying Acute and Chronic Viral Infections...1
CD8 T Cell Responses during Acute Infection...3
CD8 T Cell Responses during Chronic Infection...8
Reversing Exhaustion...14

Chapter 2: Tight Regulation of Memory CD8 T Cells Limits their Effectiveness during Sustained High Viral Load

Experimental Procedures...46

Chapter 3: Distinct and Synergistic Effects of IL-2 Therapy and PD-1 Blockade on T Cell Exhaustion and Viral Control

Material and Methods...84

Chapter 4: Discussion

Implications for Vaccine Design...97
Implications for Therapeutic Strategies...106


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