Plasmodiuminfection disrupts the T follicular helper cell response to heterologous immunization

Abstract

Naturally acquired immunity to malaria develops only after many years and repeated exposures, raising the question of whetherPlasmodiumparasites, the etiological agents of malaria, suppress the ability of dendritic cells (DCs) to activate optimal T cell responses. We demonstrated recently that B cells, rather than DCs, are the principal activators of CD4+ T cells in murine malaria. In the present study, we further investigated factors that might prevent DCs from primingPlasmodium-specific T helper cell responses. We found that DCs were significantly less efficient at taking up infected red blood cells (iRBCs) compared to soluble antigen, whereas B cells more readily bound iRBCs. To assess whether DCs retained the capacity to present soluble antigen during malaria, we measured responses to a heterologous protein immunization administered to naïve mice or mice infected withP. chabaudi. Antigen uptake, DC activation, and expansion of immunogen-specific T cells were intact in infected mice, indicating DCs remained functional. However, polarization of the immunogen-specific response was dramatically altered, with a near-complete loss of germinal center T follicular helper cells specific for the immunogen, accompanied by significant reductions in antigen-specific B cells and antibody. Our results indicate that DCs remain competent to activate T cells duringPlasmodiuminfection, but that T cell polarization and humoral responses are severely disrupted. This study provides mechanistic insight into the development of bothPlasmodium-specific and heterologous adaptive responses in hosts with malaria.