Inhibitory NK receptor expression associates with altered antimalarial function of γδ T cells

Gamma delta (γδ) T cells are important mediators of the immune response to childhood malaria. Human Vγ9+Vδ2+ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria. Engagement of the γδ T cell receptor (TCR) by phosphoantigen-bound butyrophilin molecules results in Vγ9+Vδ2+ T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated P. falciparum infection, however, leads to a reduction in circulating Vγ9+Vδ2+ 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 γδ 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 γδ T cell subsets, with Vγ9+Vδ2+ T cells exhibiting a divergent mechanism of control compared to other subsets. We found that NKG2A and KIR3DL1 expression associated with potent Vγ9+Vδ2+ 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 γδ T cells, exerting a finely tuned balance of activating and inhibitory signals to regulate the response to malaria-related antigens.