Figure 1. CD8 exhaustion during chronic toxoplasmosis.

During the later phases of chronic toxoplasmosis, concomitant with elevated mortality, encysted bradyzoites (parasites in green) undergo reactivation. This process involves T. gondii parasites undergoing stage conversion from quiescent, slow-replicating bradyzoites to highly motile, fast-replicating tachyzoites (parasites shown in red). Parasite reactivation results in disease recrudescence and eventual host mortality from toxoplasmic encephalitis. Cytokines such as IFNγ and TNFα as well cytotoxicity play an important role in controlling T. gondii infection. During chronic toxoplasmosis, CD8 T cells progressively fail to produce optimal IFNγ or TNFα and mediate cytotoxicity. Additionally, their ability to simultaneously exhibit all these functions (polyfunctionality) is lost. This is significant considering that improved pathogen control in HIV⁺ nonprogressors has been shown to be strongly correlated with CD8 polyfunctionality. This loss of CD8 polyfunctionality is concomitant with elevated PD-1 expression on CD8 T cells, decreased expression of transcription factors T-bet and Eomes, and elevated CD8 apoptosis. It is likely that an altered transcriptional profile in combination with PD-1–mediated apoptosis results in loss of polyfunctional CD8 T cells over time. This phenomenon involving graded attrition of CD8 functionality is referred to as CD8 exhaustion.