Memory regulatory T cells reprogram into protective T_FH cell-like effectors in recurrent malaria

Although people living in malaria-endemic areas experience repeated infections with Plasmodium, the role of regulatory T (T_reg) cells in recurrent malaria remains poorly understood. During a primary infection with Plasmodium, T_reg cells suppress protective immunity by inhibiting germinal center (GC) reactions, thereby impeding the control of parasitemia. In contrast, memory T_reg (mT_reg) cells remaining after the clearance of initial Plasmodium infection acquire protective functions after recall. Longitudinal studies in humans and mice show that mT_reg cells undergo antigen-driven expansion and inflammation-induced epigenetic reprogramming during reinfection to transition from FOXP3⁺ immunosuppressive cells to BCL6⁺ follicular T helper (T_FH) cell-like effectors. These mT_reg cell-derived T_FH-like cells enhance GC responses and the generation of antibodies specific to Plasmodium, ultimately facilitating Plasmodium control. Precluding such mT_reg-to-T_FH cell differentiation abolished protection. Our findings reveal a previously unrecognized adaptive plasticity in canonical mT_reg cells that enables a context-dependent functional switch from immunoregulatory to protective effectors during recurrent infections.