T-cell exhaustion: characteristics, causes and conversion

Abstract

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.

Figure 1

As exhausted T cells emerge sequential phenotypic and functional changes occur. Exhausted T cells express arrays of inhibitory molecules and distinctive patterns of cytokine receptors, transcription factors and effector molecules, which distinguish these cells from conventional effector, memory and anergic T cells. The changes depicted represent only a small subset of the overall alterations that manifest as the exhausted state develops. GranB, granzyme B; IFN-γ, interferon-γ; IL-2, interleukin-2; TNF-α, tumour necrosis factor-α.

Figure 2

T-cell exhaustion develops in a stepwise and progressive manner and can culminate in the deletion of the virus-specific T cells. The overall ensemble of T cells elicited during the initial stages of infection is comprised of a series of subsets with different functional attributes. If the infection is not brought under control then composition of this population changes as the more polyfunctional cells are lost. Sustained high viral loads result in further reductions in the functional potential of the population and severely exhausted T cells are not maintained. IFN-γ, interferon-γ; IL-2, interleukin-2; TNF-α, tumour necrosis factor-α.

Figure 3

Divergent patterns of CD8 T-cell responses develop following acute, protracted, and chronic infections. (a) Acute viral infections are rapidly contained and establish stably maintained memory T-cell pools. These memory T cells are capable of elaborating many effector functions including interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) production and a subset produce interleukin-2 (IL-2). (b) During more protracted infections the initial burst size and the functional quality of the response are often reduced, and further development of an exhausted phenotype occurs as viral loads remain high. Gradual resolution of the infection may result in a progressive resurgence of the response. (c) Exhaustion develops more rapidly and the responding T cells do not recover function if viral loads are not contained and a high-grade chronic infection ensues. (Based on Fuller et al., 6)