<i>Plasmodium</i> infection 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 whether <i>Plasmodium</i> parasites, 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 priming <i>Plasmodium</i>-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 with <i>P. chabaudi</i>. 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 during <i>Plasmodium</i> infection, but that T cell polarization and humoral responses are severely disrupted. This study provides mechanistic insight into the development of both <i>Plasmodium</i>-specific and heterologous adaptive responses in hosts with malaria.