Infect Immun. 2013 Jul 1. [Epub ahead of print]
Donor CD8+ T cells prevent Toxoplasma de-encystation but fail to rescue exhausted endogenous CD8 population
Bhadra R, Cobb DA, Khan IA.
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA.
Functional exhaustion of CD8+ T cells due to increased expression of inhibitory molecule PD-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 primarily encysted, quiescent bradyzoite to fast replicating, highly motile tachyzoite. Thus reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting IFNγ, a cytokine known to control latent toxoplasmosis, in chronically infected pre-recrudescent mice. Since CD8+ T cells (an important source of IFNγ) 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 pre-recrudescent 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, 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 suggests that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in 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.
PMID: 23817617 [PubMed - as supplied by publisher]