CD8 T cell dysfunction during chronic toxoplasmosis
Open AccessAbstract of DissertationCD8 T cell Dysfunction during Chronic Toxoplasmosis Toxoplasmic encephalitis (TE) from reactivation of chronic Toxoplasma infection is major cause of morbidity and mortality in HIV infected Toxoplasma seropositive patients. Hence understanding the mechanisms responsible for parasite reactivation in chronically infected hosts is critical for evolving strategies for the development of immunotherapeutic agents against the parasite. Effective CD8+ T cell responses, critical for control of chronic Toxoplasmosis in susceptible mice strains, paradoxically do not ensure their long-term survival. This suggests that CD8+ T cell responses during late-chronic infection are incapable of preventing mortality in infected mice. However, the mechanism underlying this apparently ineffective CD8+ T cell response during late-chronic infection has not been studied and it remains to be determined if this defect is responsible for loss of parasite control. We therefore tested whether CD8+ T cells during late-chronic toxoplasmosis become dysfunctional, as reported in some viral infections. Investigation of CD8+ T cell response revealed that CD8+ T cells during later phases of chronic toxoplasmosis are unable to mount a potent anamnestic response, a hallmark of robust adaptive immunity. Moreover CD8+ T cells from these mice exhibit a progressive increase in expression of inhibitory molecule PD-1 with concomitant parasite reactivation. In vivo blockade of PD-1 interaction with its receptor PD-L1 not only augmented polyfunctional CD8+ T cell response but it also controlled parasite recrudescence and prevented the mortality of chronically infected mice. To the best of our knowledge, this is the first report of parasite reactivation caused by PD-1 mediated CD8+ T cell dysfunction. Since immune exhaustion during chronic toxoplasmosis involves a loss of polyfunctional CD8+ T cells, we next investigated how immune exhaustion specifically mediates preferential attrition of this subset. Our study demonstrates that PD-1 is preferentially expressed on polyfunctional memory CD8+ T cells which renders them susceptible to apoptosis. In vitro blockade of PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and IFNγ+GranzymeB- memory but not effector CD8+ T cells. These findings, underscore 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. Apart from TCR signal and cytokine milieu, one of the most important factors governing CD8 response is the balance between positive signals from co-stimulatory receptors and the negative signals from inhibitory receptors. However, the role of co-stimulatory receptors during the rescue of this response has not been explored in any model of CD8 exhaustion. We demonstrate 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, we demonstrate for the first time 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. Cumulatively, these studies go a long way in understanding CD8 exhaustion in toxoplasma model and the insights afforded by them will help in designing improved vaccination strategies not only against this parasite but other persistent pathogens and tumors as well.
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