Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell-invasive merozoites

The control of Plasmodium falciparum erythrocytic parasite density is essential for protection against malaria, because it prevents pathogenesis and progression toward severe disease. P falciparum blood-stage parasite cultures are inhibited by human V gamma 9V delta 2 gamma delta T cells, but the underlying mechanism remains poorly understood. Here, we show that both intraerythrocytic parasites and the extracellular red blood cell-invasive merozoites specifically activate V gamma 9V delta 2 T cells in a gamma delta T cell receptor-dependent manner and trigger their degranulation. In contrast, the gamma delta T cell-mediated antiparasitic activity only targets the extracellular merozoites. Using perforin-deficient and granulysin-silenced T-cell lines, we demonstrate that granulysin is essential for the in vitro antiplasmodial process, whereas perforin is dispensable. Patients infected with P falciparum exhibited elevated granulysin plasma levels associated with high levels of granulysin-expressing V delta 2(+) T cells endowed with parasite-specific degranulation capacity. This indicates in vivo activation of V gamma 9V delta 2 T cells along with granulysin triggering and discharge during primary acute falciparum malaria. Altogether, this work identifies V gamma 9V delta 2 T cells as unconventional immune effectors targeting the red blood cell-invasive extracellular P falciparum merozoites and opens novel perspectives for immune interventions harnessing the antiparasitic activity of V gamma 9V delta 2 T cells to control parasite density in malaria patients. (Blood. 2011;118(26):6952-6962)