γδ-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-γ response to Plasmodium falciparum malaria

Rapid production of interferon-γ (IFN-γ) in response to malaria by the innate immune system may determine resistance to infection, or inflammatory disease. However, conflicting reports exist regarding the identity of IFN-γ-producing cells that rapidly respond to Plasmodium falciparum. To clarify this area, we undertook detailed phenotyping of IFN-γ-producing cells across a panel of naive human donors following 24-h exposure to live schizont-infected red blood cells (iRBC). Here, we show that NK cells comprise only a small proportion of IFN-γ-responding cells and that IFN-γ production is unaffected by NK cell depletion. Instead, γδ-T cells represent the predominant source of innate IFN-γ, with the majority of responding γδ-T cells expressing NK receptors. Malaria-responsive γδ-T cells more frequently expressed NKG2A compared to non-responding γδ-T cells, while non-responding γδ-T cells more frequently expressed CD158a/ KIR2DL1. Unlike long-term γδ-T cell responses to iRBC, αβ-T cell help was not required for innate γδ-T cell responses. Diversity was observed among donors in total IFN-γ output. This was positively associated with CD94 expression on IFN-γ⁺ NK-like γδ-T cells. Applied to longitudinal cohort studies in endemic regions, similar comparative phenotyping should allow assessment of the contribution of diverse cell populations and regulatory receptors to risk of infection and disease.