Under most circumstances, acute infection results in the expansion of T lymphocytes specific for the inciting pathogen, clearance of the pathogen, and the development of memory T cells able to eliminate that pathogen more effectively upon re-exposure of the host. However, some pathogens cannot be efficiently cleared from infected hosts and persist throughout the lifetime of the organism, despite the formation of pathogen-specific T cells. Examples of such pathogens include human immunodeficiency virus and hepatitis viruses B and C. These persistent infections result in chronic antigen exposure, which, instead of continuing to induce maximal productive T-cell responses, leads to the generation of “exhausted” T cells that have reduced ability to kill and produce cytokines in response to infection. The development of T-cell memory and the exhaustion response are initiated in similar ways, with the formation of cells that are capable of responding to antigen challenge through proliferation and the secretion of cytokines. However, during exhaustion, the persistence of pathogen causes T cells to become increasingly less responsive to stimulation. At early time points in this process, exhausted CD8+ T cells lose the ability to secrete IL-2 or TNF-α and cannot induce cytolysis of infected host cells. At later time points, CD8+ T cells become completely unresponsive and ultimately undergo apoptosis. The induction of exhaustion is thought to represent a functional adaption that permits some degree of control of chronic infection while limiting immune-induced tissue damage.
Concurrent with the loss of functional responses, exhausted cells upregulate inhibitory cell surface receptors. The best studied of these inhibitory receptors is programmed death 1 (PD-1), which binds its ligands, PD-L1 and PD-L2, expressed on activated macrophages and other APCs. Engagement of PD-1 dampens the T-cell response, likely by recruiting phosphatases that oppose the PTKs necessary for T-cell activation. PD-1 is normally expressed on T cells after initial activation, presumably as a means to prevent excessive responses, and is then downregulated as T cells acquire a memory phenotype after the pathogen clearance. Exhausted T cells, however, continue to express this inhibitory receptor.10 Early during exhaustion, PD-1 blockade is capable of reversing T-cell exhaustion in experimental models to some degree; however, epigenetic changes in T cells that take place during exhaustion prevent the T cells from ever regaining full function. Moreover, as chronic antigen exposure continues, other inhibitory receptors such as Lag-3 and Tim3 become expressed, further diminishing the functional potential of the exhausted T cell. Blockade of PD-1 with these other receptors has been shown to improve T-cell responsiveness, even at later stages of exhaustion. Therapeutic targeting of the PD-1 axis and other key inhibitory receptors is an exciting new avenue for immunotherapy against malignancies (see later) and chronic infections.
