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.