Vγ9Vδ2 T Cells Kill Intraerythrocytic P. Falciparum in a Granzyme B Dependent Manner

Abstract

Malaria, caused by Plasmodium falciparum, is one of the most serious infectious diseases and a leading cause of morbidity in the developing world. Humoral immunity against blood stage malaria has been studied for decades. Now emerging evidence suggests that cytotoxic cells also contribute to the defense against intraerythrocytic parasites. P. falciparum infects mature red blood cells (RBCs) which lack classical HLA expression, thereby escaping from the surveillance of conventional T cells. P. falciparum infected patients show an expansion of non-MHC restricted innate-like Vγ9Vδ2 T cells and elevation of the antimicrobial protein granulysin in their blood, suggesting this subset of killer cells might respond to malaria infection. However, whether Vγ9Vδ2 T cells kill intraerythrocytic P. falciparum remains unknown. We found that Vγ9Vδ2 T cells release their cytotoxic granules when exposed to P. falciparum-infected RBCs. Both Vγ9Vδ2 T cells and purified granulysin and granzyme B lyse infected RBCs, suggesting that Vγ9Vδ2 T cells kill the intraerythrocytic parasites in a granulysin and granzyme B dependent manner. Proteomics analysis to identify GzmB substrates shows that GzmB disrupts biosynthetic and metabolic pathways that are essential for the survival of P. falciparum.