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

Abstract

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.