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.
Nature Immunology published a clinical update in Infectious Disease on 22 Jun 2026.
The item focuses on Memory regulatory T cells reprogram into protective T FH cell-like effectors in recurrent malaria.
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