T cell exhaustion during persistent viral infections

Abstract

Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control.

Keywords: Cytokines; Immunity; Inhibitory receptors; Persistent infections; T cell exhaustion.

Figure 1. CD8 T cells can adopt a spectrum of exhausted states

The levels of viral antigen and availability of CD4 T cells are key determinants of the extent of CD8 T cell exhaustion. CD4 T cells also succumb to exhaustion, which can result in further deterioration of the anti-viral CD8 T cell response. CD8 T cell exhaustion is characterized by the step-wise and progressive loss of effector capabilities, the sustained upregulation of inhibitory receptors, and the loss of self-renewal abilities. which compromise viral control. Severely exhausted T cells may undergo apoptosis and become deleted from the chronically infected host.

Figure 2. NK cells can promote T cell exhaustion during chronic infections

NK cells can target and kill activated CD4 T cells during the early stages of viral infections, removing vital helper functions, thereby fostering the development of CD8 T cell exhaustion. NK cells may also directly target anti-viral CD8 T cells, reducing their availability to control the infection and thus also promoting exhaustion. The targeted depletion of NK cells can save the anti-viral T cell responses and permit viral clearance.

Figure 3. Strategies for rejuvenating exhausted T cells

Inhibiting suppressive cytokines, blocking inhibitory receptors, cytokine treatments, and molecular reprogramming have all been shown to help restore the functions of exhausted T cells. Combination approaches are also successful.