Effector Phenotype of Plasmodium falciparum-Specific CD4+ T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations

Abstract

Background. Mechanisms mediating immunity to malaria remain unclear, but animal data and experimental human vaccination models suggest a critical role for CD4+ T cells. Advances in multiparametric flow cytometry have revealed that the functional quality of pathogen-specific CD4+ T cells determines immune protection in many infectious models. Little is known about the functional characteristics of Plasmodium-specific CD4+ T-cell responses in immune and nonimmune individuals. Methods. We compared T-cell responses to Plasmodium falciparum among household-matched children and adults residing in settings of high or low malaria transmission in Uganda. Peripheral blood mononuclear cells were stimulated with P. falciparum antigen, and interferon γ (IFN-γ), interleukin 2, interleukin 10, and tumor necrosis factor α (TNF-α) production was analyzed via multiparametric flow cytometry. Results. We found that the magnitude of the CD4+ T-cell responses was greater in areas of high transmission but similar between children and adults in each setting type. In the high-transmission setting, most P. falciparum-specific CD4+ T-cells in children produced interleukin 10, while responses in adults were dominated by IFN-γ and TNF-α. In contrast, in the low-transmission setting, responses in both children and adults were dominated by IFN-γ and TNF-α. Conclusions. These findings highlight major differences in the CD4+ T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.