Inhibitory NK receptors regulate the γδ T cell response to malaria

Gamma delta (γδ) T cells are important mediators of the immune response to childhood malaria infection. Human Vγ9 ⁺ Vδ2 ⁺ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria infection. 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 malaria 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.