| Shrnutí: | Background: Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against divers pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP) and circumsporozoite (CS) protein, major vaccine candidate antigens, were measured, as were frequencies of CD4^+ CD25^high T cells, which may suppress immunity, and CD56^+ NK cells and γδ T cells, which may be effectors or may modulate immunity. Methodology and Principal Findings: 112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNγ ELISPOT appproach, whilst CD4^+ CD25^high T cells were established early in life (<5 years) in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNγ ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p=0.028). This was not seen for CS responses. Higher numbers of CD4^+ CD25^high T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p=0.039). Conclusions: These data demonstrate a role for central memory T cells in natural malaria immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also suggest that CD4^+ CD25^high T cells may negatively affect naturally acquired malarial immunity.
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