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.

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

“…Epidemiological studies suggest that repeatedly exposed individuals eventually develop protective immunity (such that adults in endemic areas rarely develop CM), which may be characterized by the ability to control parasite replication (keeping parasite densities below the critical threshold for induction of inflammation or impairment of cerebral blood flow), to prevent pRBC sequestration or to regulate the inflammatory process (ArtavanisTsakonas et al 2003 ;Walther et al 2009). …”

Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens

“…Recent studies show that T regs can modify susceptibility to disease (77,78) and contribute to whether the host immune responses are protective or pathological in response to infection with P. falciparum parasites (73,(79)(80)(81)(82). The nature of the initial exposure to malaria Ags likely affects the potentially diverse roles assumed by T regs in malaria infection.…”

Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/–) ex vivo and after in vitro restimulation with malaria antigens

“…As for conventional T cells, it has been shown that the majority of CD4 T cells with regard to the expression of CCR and apoptotic molecules and suggest that CD25, rather than being a marker of Treg per se, is a marker of activated Treg. Given our interest in Treg function during malaria infection [38,[44][45][46][47], we further aimed to study these markers in relation to Treg activation status in vitro, using Plasmodium falciparum schizont extract (PfSE). Importantly, we show that -irrespective of the culture conditions -the phenotype of FOXP3 1 T cells is modified when they are kept in in vitro culture, affecting both expression of CCR and molecules involved in apoptosis, indicating a need for caution when comparing data from in vitro and ex vivo studies.…”