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

Area of Science:

• Immunology
• Infectious Diseases
• Malariology

Background:

• Recurrent Plasmodium infections are common in endemic areas, but the role of regulatory T (Treg) cells is unclear.
• During primary Plasmodium infection, Treg cells suppress protective immunity and germinal center (GC) reactions, hindering parasite control.
• Memory Treg (mTreg) cells, persisting after initial infection, may have different functions upon reinfection.

Purpose of the Study:

• To investigate the role and function of mTreg cells during recurrent Plasmodium infections.
• To understand the plasticity and adaptive potential of mTreg cells in the context of malaria reinfection.
• To elucidate the mechanisms by which mTreg cells influence adaptive immunity and parasite control.

Main Methods:

• Longitudinal studies in human and mouse models of recurrent Plasmodium infection.
• Analysis of mTreg cell expansion, epigenetic reprogramming, and differentiation.
• Assessment of GC reactions, antibody generation, and Plasmodium control.

Main Results:

• mTreg cells expand antigen-specifically and undergo epigenetic reprogramming during reinfection.
• mTreg cells transition from immunosuppressive FOXP3+ cells to follicular T helper (Tfh)-like BCL6+ effectors.
• These mTreg-derived Tfh-like cells enhance GC responses and Plasmodium-specific antibody production, improving parasite control.
• Blocking mTreg to Tfh cell differentiation abrogated protective immunity.

Conclusions:

• mTreg cells exhibit adaptive plasticity, switching function from immunosuppressive to protective during recurrent malaria.
• This functional switch enhances adaptive immunity, facilitating Plasmodium control through improved antibody responses.
• Findings reveal a novel mechanism of immune regulation and protection in the context of repeated parasitic infections.