Th1-like Plasmodium-specific memory CD4+ T cells unexpectedly support humoral immunity

Effector T-cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium -specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T-cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium -specific memory CD4 T-cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B-cell help and protection following transfer, characteristics that are enhanced following ligation of the T-cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium -specific memory CD4 T-cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.