Distinct Roles for FOXP3+ and FOXP3− CD4+ T Cells in Regulating Cellular Immunity to Uncomplicated and Severe Plasmodium falciparum Malaria

Abstract

Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to pathogenesis of severe malaria. To determine whether this balance is maintained by classical regulatory T cells (CD4⁺ FOXP3⁺ CD127^−/low; Tregs) we compared cellular responses between Gambian children (n = 124) with severe Plasmodium falciparum malaria or uncomplicated malaria infections. Although no significant differences in Treg numbers or function were observed between the groups, Treg activity during acute disease was inversely correlated with malaria-specific memory responses detectable 28 days later. Thus, while Tregs may not regulate acute malarial inflammation, they may limit memory responses to levels that subsequently facilitate parasite clearance without causing immunopathology. Importantly, we identified a population of FOXP3⁻, CD45RO⁺ CD4⁺ T cells which coproduce IL-10 and IFN-γ. These cells are more prevalent in children with uncomplicated malaria than in those with severe disease, suggesting that they may be the regulators of acute malarial inflammation. While Tregs have been implicated in regulation of the immune response to chronic infections, their potential in determining disease outcome in acute infections is unclear. In this study we have found that Tregs are unable to control the florid inflammation during acute, severe P. falciparum malaria infections, suggesting that this component of the immunoregulatory arsenal may be rapidly overwhelmed by virulent infections. Further, we identified, for the first time in an acute human infection, a population of IL-10-producing Th-1 effector cells and found that IL-10-producing Th-1 cells were associated with development of uncomplicated as opposed to severe malaria, leading us to suggest that such “self-regulating” Th-1 cells may contribute to clearing malaria infections without inducing immune-mediated pathology. In addition, we found evidence that malaria-induced Tregs may limit the magnitude of malaria-specific memory responses detectable 28 days later, which may reduce the risk of immune-mediated pathology upon reinfection and may explain how immunity to severe disease can be gained after as little as one or two infections. We conclude that vaccines designed to induce cell-mediated responses should be assessed for their ability to induce IL-10 producing Th-1 cells and Tregs.