γδ T Cells Kill Plasmodium falciparum in a Granzyme- and Granulysin-Dependent Mechanism during the Late Blood Stage

Abstract

Plasmodium spp., the causative agent of malaria, have a complex life cycle. The exponential growth of the parasites during the blood stage is responsible for almost all malaria-associated morbidity and mortality. Therefore, tight immune control of the intraerythrocytic replication of the parasite is essential to prevent clinical malaria. Despite evidence that the particular lymphocyte subset of gd T cells contributes to protective immunity during the blood stage in naive hosts, their precise inhibitory mechanisms remain unclear. Using human PBMCs, we confirmed in this study that gd T cells specifically and massively expanded upon activation with Plasmodium falciparum culture supernatant. We also demonstrate that these activated cells gain cytolytic potential by upregulating cytotoxic effector proteins and IFN-g. The killer cells bound to infected RBCs and killed intracellular P. falciparum via the transfer of the granzymes, which was mediated by granulysin in a stage-specific manner. Several vital plasmodial proteins were efficiently destroyed by granzyme B, suggesting proteolytic degradation of these proteins as essential in the lymphocyte-mediated death pathway. Overall, these data establish a granzyme-and granulysin-mediated innate immune mechanism exerted by gd T cells to kill late-stage blood-residing P. falciparum.

γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde

“…As a lethal neurological complication of Plasmodium infection, cerebral malaria (CM) is responsible for the majority of child mortality (103). gdT cells can protect against Plasmodium infection by killing extracellular merozoites and intracellular late-stage parasites and regulating other lymphocytes such as ab T cells and dendritic cells in both human and Plasmodium infection mouse model (104)(105)(106)(107)(108)(109)135). However, IFN-g producing gd T cells in the liver stage of infection are responsible for experimental cerebral malaria (ECM).…”

Human γδ TCR Repertoires in Health and Disease

“…Upon infection with Plasmodium species, proliferation and phenotypic changes of γδ T cells have been observed and extensively reviewed elsewhere [99][100][101][102]. Importantly, Vγ9Vδ2 + T cells that recognize pAgs produced by the parasite as well as non-Vγ9Vδ2 + T cells seem to be implied in the γδ T cells response during malaria [103,104].…”

Mapping T cell activation and differentiation at single cell resolution in naive hosts infected withPlasmodium vivax

“…Our aim was to track the acute phase response through time to ask how P. vivax activates the innate immune system and the consequences for T cell activation and differentiation. T cells are uniquely placed to orchestrate the host response to malaria as they enter inflamed tissues, direct myeloid cell function, provide essential B cell help, and even directly kill Plasmodium infected red cells and reticulocytes (13,28). However, aberrant T cell responses can be pathological (29)(30)(31) and therefore mapping the T cell response in naive hosts (who are most susceptible to disease) was a priority.…”