Combining Regulatory T Cell Depletion and Inhibitory Receptor Blockade Improves Reactivation of Exhausted Virus-Specific CD8+ T Cells and Efficiently Reduces Chronic Retroviral Loads

Kirsten K. Dietze,Jia Liu,Ulf Dittmer,Freya Kretzmer,Gennadiy Zelinskyy,Simone Schimmer,Daniel C. Douek

doi:10.1371/journal.ppat.1003798

Abstract

Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8+ T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8+ T cells and expansion of regulatory T cells (Tregs) that suppress CD8+ T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8+ T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8+ T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8+ T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases.

Highlights

IntroductionIn several chronic virus infections, like HIV or hepatitis C virus (HCV) in humans, the virus evades destruction by CD8+ T cells
Cytotoxic CD8+ T cells are crucial for the control of most virus infections
The T cell exhaustion is mediated by two main mechanisms, the expression of inhibitory receptors on CD8+ T cells and virus-induced expansion of regulatory T cells (Tregs), which suppress CD8+ T cell activity

Summary

Introduction

In several chronic virus infections, like HIV or hepatitis C virus (HCV) in humans, the virus evades destruction by CD8+ T cells These infections are associated with an appearance of functionally exhausted virus-specific effector cells, which reflects an important mechanism of immune evasion and likely contributes to the inability of the host to eliminate the pathogen. There are two main mechanisms described in the context of functional disability of CD8+ T cells One of these mechanisms appears to be the induction of Tregs, a specialized CD4- and Foxp3-expressing T cell subset that controls immune responses by suppressing the proliferation and functions of effector T cells. A transient depletion of Tregs in an established chronic infection improved anti-viral immune responses in part by reactivating previously suppressed and functionally exhausted CD8+ T cells and thereby significantly reduced chronic viral set points [5]

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Conclusion