Unconventional T cell immunity in malaria

Key Takeaways:

• γδ T cells play an important role in the human immune response to malaria.
• Adaptive-like γδ T cells are clonally selected in the context of Malaria infection and display reactivity to P. falciparum parasites.
• RNA-based γδ TCR repertoire analysis allows the study of clonal expansion of specific T cell populations.

Abstract

Repeated Plasmodium falciparum infections drive the development of clinical immunity to malaria in humans, however, the immunological mechanisms that underpin this response are only partially understood. We investigated the impact of repeated P. falciparum infections on human γδ T cells in the context of natural infection in Malian children and adults, as well as serial controlled human malaria infection (CHMI) of U.S. adults, some of whom became clinically immune to malaria. We found clonally expanded cytotoxic-γδ T cells were enriched in the γδ T cell compartment of Malian subjects. Malaria-naïve U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the γδ T cell repertoire. Specifically, innate-like γδ T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas a population of adaptive-like γδ T cells increased in frequency with repeated infections. Moreover, repeated P. falciparum infection drove waves of clonal selection in the γδ TCR repertoire that coincided with the differentiation of γδnaive cells into cytotoxic-γδeffector cells. Finally, γδ T cells from malaria-exposed Malian and U.S. individuals were licensed for reactivity to P. falciparum parasites in vitro. Together, our study indicates that repeated P. falciparum infection drives the clonal expansion of an adaptive γδ T cell repertoire and establishes a new role for γδ T cells in the human immune response to malaria.

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