Memory Regulatory T cells in Recurring Malaria

PROJECT SUMMARY Regulatory T cells or ‘Tregs’ play a critical role in our health and well-being by suppressing over- exuberant immune responses. Antigen-specific Tregs, like other T cell subsets, are maintained for prolonged periods in the host as memory Tregs (mTregs). These are possibly recalled to protect against the immunopathology associated with repeated encounters with the same antigen. Initial observations supporting this notion in viral infection models have generated immense interest, especially from the fields of autoimmune diseases, allergy medicine, maternal-fetal medicine, or recurrent infectious diseases, where repeated exposures to self or non-self antigens are fundamental. Malaria, caused by Plasmodium, is one such disease, where humans residing in endemic areas get repeatedly infected. However, Tregs are known to impede the protective immune responses against Plasmodium during a primary infection. Therefore, we expected the mTregs also to behave similarly by hindering protection in both humans and mice following Plasmodium re-exposure. Surprisingly, humans possessing higher frequencies of mTregs exhibited reduced parasite loads upon reinfection. In mice also, the presence of mTregs promoted better control of repeat infections with Plasmodium. These findings suggested that Tregs behave differently in primary and secondary infections during malaria and challenged the fundamental concept of functional memory in T cells. The primary objective of this research proposal is to determine the mechanisms underlying mTregs-mediated protection and function in recurrent malaria. Our preliminary experiments suggest that the mTregs generated by Plasmodium infection transition to Tfh-like cells that promote anti-Plasmodium immunity. Our central hypothesis is that mTregs undergo inflammation-induced epigenetic modifications to enable their pheno-conversion into Tfh-like cells during recall and promote the generation of robust germinal center (GC) reaction and antibody responses. This would facilitate better control of Plasmodium reinfection. We will test this hypothesis by determining the molecular mechanism of the transition of mTregs to Tfh-like cells (Specific Aim1) and resolving how such a transition would promote immunity to Plasmodium reinfection (Specific Aim 2). We think that the mTregs maintained in malaria-experienced individuals are a transitionary state of Tfh cells, allowing such cells to survive for prolonged periods in the host. The completion of our proposed studies would provide new insights into how mTregs can impact disease outcomes in recurrent infections such as malaria, where reinfections constitute the majority of the clinical cases in humans.