γδ T cells in malaria: a double‐edged sword

The pathogenic role of γδ T cells in experimental cerebral malaria (ECM) is dependent on the liver stage of infection. In the presence of IFN‐γ‐producing γδ T cells, parasites that egress the liver are more virulent and lead to ECM. In humans, Vγ9Vδ2 T cells recognize soluble Plasmodium phosphoantigens and become activated, producing IFN‐γ and inducing CM. After repeated parasite exposure, Vγ9Vδ2 T cells decrease production of pro‐inflammatory cytokines, which associates with clinical tolerance. Malaria remains a devastating global health problem, resulting in many annual deaths due to the complications of severe malaria. However, in endemic regions, individuals can acquire ‘clinical immunity’ to malaria, characterized by a decrease in severe malaria episodes and an increase of asymptomatic Plasmodium falciparum infections. Recently, it has been reported that tolerance to ‘clinical malaria’ and reduced disease severity correlates with a decrease in the numbers of circulating Vγ9Vδ2 T cells, the major subset of γδ T cells in the human peripheral blood. This is particularly interesting as this population typically undergoes dramatic expansions during acute Plasmodium infections and was previously shown to play antiparasitic functions. Thus, regulated γδ T‐cell responses may be critical to balance immune protection with severe pathology, particularly as both seem to rely on the same pro‐inflammatory cytokines, most notably TNF and IFN‐γ. This has been clearly demonstrated in mouse models of experimental cerebral malaria (ECM) based on Plasmodium berghei ANKA infection. Furthermore, our recent studies suggest that the natural course of Plasmodium infection, mimicked in mice through mosquito bite or sporozoite inoculation, includes a major pathogenic component in ECM that depends on γδ T cells and IFN‐γ production in the asymptomatic liver stage, where parasite virulence is seemingly set and determines pathology in the subsequent blood stage. Here, we discuss these and other recent advances in our understanding of the complex—protective versus pathogenic—functions of γδ T cells in malaria.