Inhibitory NK receptors regulate the γδ T cell response to malaria

Gamma delta ({gamma}{delta}) T cells are important mediators of the immune response to childhood malaria infection. Human V{gamma}9+V{delta}2+ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria infection. Engagement of the {gamma}{delta} T cell receptor (TCR) by phosphoantigen-bound butyrophilin molecules results in V{gamma}9+V{delta}2+ T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated malaria infection, however, leads to a reduction in circulating V{gamma}9+V{delta}2+ T cells and upregulation of immunomodulatory molecules, including NK receptors, that correlates with less severe symptoms upon infection. We explore phenotypic and functional differences of {gamma}{delta} T cells in Ugandan children with high versus low malaria exposure, utilizing high-parameter spectral flow cytometry analysis of PBMCs. We observed significant differences in expression of inhibitory NK receptors - KIR2DL1, KIR2DL2/3, KIR3DL1, LILRB1, and NKG2A - on {gamma}{delta} T cell subsets, with V{gamma}9+V{delta}2+ T cells exhibiting a divergent mechanism of control compared to other subsets. We found that NKG2A and KIR3DL1 expression associated with potent V{gamma}9+V{delta}2+ T cell responses to TCR- and Fc receptor (FcR)-mediated stimulation while KIR2DL1, KIR2DL2/3 and LILRB1 associated with reduced degranulation and cytokine production. These results identify a new role for inhibitory NK receptors expressed on {gamma}{delta} T cells, exerting a finely tuned balance of activating and inhibitory signals to regulate the response to malaria-related antigens. AUTHOR SUMMARYMalaria remains one of the deadliest infectious diseases, disproportionately affecting young children in sub-Saharan Africa who succumb to sequelae of Plasmodium falciparum infection. However, children living in highly endemic areas experience repeated malaria infection and develop naturally acquired-but not sterilizing-immunity which leads to an asymptomatic reinfection pattern. The immune factors that determine the balance of inflammatory and tolerogenic functions seen in non-sterilizing malaria immunity are yet to be fully understood. Here, we focus on the phenotypic and functional differences in one cell type between children with a history of low versus high malaria exposure. We identified a group of inhibitory surface receptors that improved the antimalarial function of this cell, and another group that worsened their function. Our study clarifies the immune landscape in highly malaria-exposed individuals and illuminates one potential system of regulating the cellular response to repeat infection.