Naturally-occurring CD4+Foxp3+ regulatory T cells (nTreg) play a central role in maintaining immune self-tolerance as well as modulating immunity towards pathogens. Pathogens may establish chronic infections in immunocompetent hosts by engaging nT reg in order to promote immunosuppression. The goal of the research described here is to test the hypothesis that nTreg modulate protective immunity to malaria, and consequentially affect susceptibility to the parasite. To investigate this question, the functional dynamics of CD4+Foxp3 + nTreg cells were evaluated in mice infected with blood-stage Plasmodium chabaudi AS. Adoptive transfer of nTreg to infected wild-type C57BL/6 (B6) mice or infection of transgenic B6 mice over-expressing Foxp3 resulted in increased parasitemia and reduced survival compared to control mice. Moreover, while resistant B6 mice exhibited decreased splenic nT reg frequencies at day 7 post infection, susceptible A/J mice maintained high numbers of nTreg at this time. Investigation of the effects of nTreg regulation on immune cell function in P. chabaudi AS-infected mice revealed that increased nTreg frequencies led to decreased malaria-specific lymphoproliferation and increased systemic levels of IL-10. Unlike B6 mice, increased splenic nTreg frequencies in infected A/J mice correlated with decreased effector T cell proliferation and IFN-gamma secretion, decreased B cell and NK cell proliferation as well as deficient IFN-gamma secretion by NK cells. Finally, nTreg proliferated within infected sites in both B6 and A/J mice, albeit to a greater extent in susceptible A/J mice. Altogether, these results demonstrate that nTreg suppressed anti-malarial immunity, and in turn promoted parasite growth and persistence.

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