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-gamma (IFN-gamma) 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-gamma-producing cells that rapidly respond to Plasmodium falciparum. To clarify this area, we undertook detailed phenotyping of IFN-gamma-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-gamma-responding cells and that IFN-gamma production is unaffected by NK cell depletion. Instead, gamma delta-T cells represent the predominant source of innate IFN-gamma, with the majority of responding gamma delta-T cells expressing NK receptors. Malaria-responsive gamma delta-T cells more frequently expressed NKG2A compared to non-responding gamma delta-T cells, while non-responding gamma delta-T cells more frequently expressed CD158a/KIR2DL1. Unlike long-term gamma delta-T cell responses to iRBC, alpha beta-T cell help was not required for innate gamma delta-T cell responses. Diversity was observed among donors in total IFN-gamma output. This was positively associated with CD94 expression on IFN-gamma(+) NK-like gamma delta-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.