In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8 + T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8 + T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue. Blockade of the PD-1–PDL-1 pathway reinvigorates this suboptimal CD8 + T-cell response, resulting in control of parasite reactivation and prevention of mortality in chronically infected animals. To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8 + T-cell dysfunction and parasite reactivation.

Khan et al. demonstrate that in chronic toxoplasmosis, CD4 T cell–intrinsic expression of Blimp-1 results in progressive exhaustion, which in turn contributes to CD8 T cell exhaustion and poor pathogen control.

CD8 exhaustion mediated by inhibitory PD-1-PD-L1 pathway occurs in several chronic infections including toxoplasmosis. While blockade of PD-1-PD-L1 pathway revives this response, the role of co-stimulatory receptors involved in this rescue has not been ascertained in any model of CD8 exhaustion. This is the first report which demonstrates that one such co-stimulatory pathway, CD40-CD40L, plays a critical role during rescue of exhausted CD8 T cells. Blockade of this pathway abrogates the ameliorative effects of αPD-L1 treatment on CD8 T cells. Additionally, this is the first report which demonstrates, in an infectious disease model, that CD8 intrinsic CD40 signaling is important for optimal CD8 polyfunctionality, proliferation, T-bet upregulation and IL-21 signaling, albeit in the context of CD8 rescue. The critical role of CD40 during the rescue of exhausted CD8 T cells may provide a rational basis for designing novel therapeutic vaccination approaches.

We reported earlier that during chronic toxoplasmosis CD8 + T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8 + T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ + /granzyme B − memory but not effector CD8 + T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8 + T-cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections. Effective

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