title: gammadelta-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-gamma response to Plasmodium falciparum malaria.
abstract: 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, gammadelta-T cells represent the predominant source of innate IFN-gamma, with the majority of responding gammadelta-T cells expressing NK receptors. Malaria-responsive gammadelta-T cells more frequently expressed NKG2A compared to non-responding gammadelta-T cells, while non-responding gammadelta-T cells more frequently expressed CD158a/KIR2DL1. Unlike long-term gammadelta-T cell responses to iRBC, alphabeta-T cell help was not required for innate gammadelta-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 gammadelta-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.
authors.affiliation: Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Marthe C
authors.initials: MC
authors.lastname: D'Ombrain
authors.forename: Diana S
authors.initials: DS
authors.lastname: Hansen
authors.forename: Ken M
authors.initials: KM
authors.lastname: Simpson
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology*; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: C527054:KLRC1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma