Memory Regulatory T Cells Reprogram into Protective Tfh-like Effectors in Recurrent Malaria

Abstract Although people living in malaria-endemic areas experience repeated infections with Plasmodium , the role of regulatory T cells (Tregs) in recurrent malaria remains poorly understood. During a primary infection with Plasmodium , Tregs suppress protective immunity by inhibiting germinal center (GC) reactions, thereby impeding the control of parasitemia. In contrast, we demonstrate here that memory Tregs (mTregs) remaining after the clearance of initial Plasmodium infection acquire protective functions upon recall. Relying on longitudinal studies in humans and mice, we show that mTregs undergo antigen-driven expansion and inflammation-induced epigenetic reprogramming during reinfection to transition from Foxp3 + immunosuppressive cells to Bcl6 + follicular T helper (Tfh)-like effectors. These mTreg-derived Tfh-like cells enhance GC responses and the generation of Plasmodium -specific antibodies, ultimately facilitating Plasmodium control. Precluding such mTreg-to-Tfh differentiation abolished protection. Our findings reveal a previously unrecognized adaptive plasticity in canonical mTregs that enables a context-dependent functional switch from immunoregulatory to protective effectors during recurrent infections.