CD4+ T follicular helper (Tfh) cells dominate the acute response to a blood-stage Plasmodium infection and provide signals to direct B cell differentiation and protective antibody expression. We studied antigen-specific CD4+ Tfh cells responding to Plasmodium infection in order to understand the generation and maintenance of the Tfh response. We discovered that a dominant, phenotypically stable, CXCR5+ Tfh population emerges within the first 4 d of infection and results in a CXCR5+ CCR7+ Tfh/central memory T cell response that persists well after parasite clearance. We also found that CD4+ T cell priming by B cells was both necessary and sufficient to generate this Tfh-dominant response, whereas priming by conventional dendritic cells was dispensable. This study provides important insights into the development of CD4+ Tfh cells during Plasmodium infection and highlights the heterogeneity of antigen-presenting cells involved in CD4+ T cell priming.

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