Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire

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 gamma delta 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. In contrast to the predominant V delta 2(+) T cell population in malaria-naive Australian individuals, clonally expanded cytotoxic V delta 1(effector) T cells were enriched in the gamma delta T cell compartment of Malian subjects. Malaria-naive U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the gamma delta T cell repertoire. Specifically, innate-like V delta 2(+) T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas V delta 1(+) T cells increased in frequency with repeated infections. Moreover, repeated P. falciparum infection drove waves of clonal selection in the V delta 1(+) T cell receptor repertoire that coincided with the differentiation of V delta 1(naive) T cells into cytotoxic V delta 1(effector) T cells. V delta 1(+) T cells of 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 gamma delta T cell repertoire and establishes a role for V delta 1(+) T cells in the human immune response to malaria.

Automated summary

Repeated Plasmodium falciparum infections drive clonal expansion of an adaptive gamma delta T cell repertoire, with V delta 1(+) T cells playing a role in human immune response to malaria in Malian and U.S. individuals.