Tolerance and exhaustion: defining mechanisms of T cell dysfunction

Abstract

CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal.

Keywords: CD8 T cells; T cell differentiation; T cell dysfunction; chronic infection; exhaustion; self-tolerance; tumors.

Figure 1

T cell differentiation of naïve CD8 T cells results in either functional T cell memory or T cell dysfunction as reflected by self-tolerance or exhaustion in chronic infections. Functional memory: When naïve CD8 T cells encounter (foreign) antigen in a stimulatory and inflammatory context (e.g. acute infection), T cells differentiate into effector and eventually into memory T cells. Tolerance: Peripheral self-reactive CD8 T cells that encounter self-antigen in a tolerogenic context acquire a program of functional unresponsiveness. Tolerant T cells can be transiently rescued by inducing cell proliferation, e.g. by cytokines (IL-2, IL-15) or lymphopenia. However, once proliferation stops, rescued self-reactive T cells are re-tolerized. If self-tolerant T cells can be permanently reprogrammed and rescued remains to be determined. Exhaustion: Virus-specific T cells initially acquire some effector functions early during chronic infections, but, due to persistence of viral antigen and inflammation, T cells become progressively exhausted. Exhausted T cells represent a heterogeneous T cell population containing T-bet^hiPD-1^int and Eomes^hiPD-1^hi subpopulations (see text). T-bet^hiPD-1^int but not Eomes^hiPD-1^hi exhausted T cells can be functionally rescued by PD-1 blockade.

Figure 2

Factors mediating exhaustion in chronic infections and tumor-induced T cell dysfunction. Exhausted virus-specific CD8 T cells in chronic infections (left) and dysfunctional tumor-infiltrating CD8 T cells (TIL, right) exhibit an `exhausted' state induced by high viral or tumor antigen load and immunosuppressive factors. `Exhausted' T cells in both settings share phenotypic and functional characteristics, including the expression of inhibitory receptors such as PD-1, LAG-3, 2B4, TIM-3, CTLA-4. However, TIL can represent a heterogeneous cell population with distinct individual `states' of dysfunction. Such dysfunctional states can be mediated by cell-intrinsic programs, including a tolerance program imprinted in self/tumor antigen-specific T cells, or programs induced in tumor-specific T cells that encounter tumor antigen early during a pre-malignant non-inflammatory phase of tumor development (red). Consequently, depending on the nature of the T cells and the microenvironment in which they must function, TIL might require different immunotherapeutic strategies to restore cell function. Abbreviations: MDSC = myeloid-derived suppressor cells; T_reg = regulatory CD4 T cells; TGF-β = transforming growth factor β; NOS = Nitric Oxide Synthase; ROS = reactive oxygen species.