Donor CD8+ T cells prevent Toxoplasma de-encystation but fail to rescue exhausted endogenous CD8 population (original) (raw)
Functional exhaustion of CD8 ؉ T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-␥), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8 ؉ T cells (an important source of IFN-␥) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8 ؉ T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8 ؉ T cells. While the transfer of immune CD8 ؉ T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8 ؉ T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8 ؉ T cells fail to become long-lived, one of the cardinal features of memory CD8 ؉ T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8 ؉ T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.
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