T cell exhaustion during chronic viral infections. Virus-specific CD8 T cells posses multiple functions including production of IFN-γ, TNF-α, IL-2, cytotoxicity, antigen-driven proliferation, and resistance to apoptosis. During chronic infections, functions can be exhausted. Exhaustion represents a spectrum from mild (Partial exhaustion I: little IL-2 and poor TNF-α and cytotoxicity) to moderate (Partial exhaustion II: modestly defective IFN-γ, cytotoxicity, and little IL-2 or TNF-α) to severe (Full exhaustion: lack of IFN-γ, TNF-α, IL-2, and cytotoxicity). Finally, physical deletion (apoptosis) of T cells occurs. Proliferative potential decreases concomitantly with the loss of other functions while apoptosis increases. Antigen and CD4 help strongly influence exhaustion; as antigen increases and/or CD4 help decreases, virus-specific T cells become more exhausted. Recent studies now identify the PD-1–PD-L pathway as a key regulator of exhaustion. Increased expression of PD-1 by virus-specific T cells, and PD-L1 by APCs, leads to more severe exhaustion during chronic viral infection.

Reinvigorating exhausted T cells. (A) Microbial products and cytokines produced in response to microbes activate APCs and stimulate expression of CD80 and CD86. Engagement of CD28 by CD80/CD86 stimulates the expansion and differentiation of naive T cells into effector T cells. (B) Effector T cells eliminate the invading pathogens by secreting cytokines and killing infected cells. (C) Upon resolution of infection, effector T cells give rise to long-lived protective memory T cells. (D) However, during chronic infection, T cells lose function and the ability to proliferate and become functionally exhausted. Exhausted T cells express high levels of PD-1. (E) Blockade of interactions between PD-1 and its ligands can reinvigorate T cells to expand and regain effector functions, including cytokine production and cytolysis.