Differential IL-18 Dependence of Canonical and Adaptive NK Cells for Antibody Dependent Responses to P. falciparum

Abstract

Human adaptive natural killer (NK) cells have diminished reliance on accessory cytokines for their activation whilst being efficiently activated by infected host cells in conjunction with pathogen specific antibodies. Here, we show that potent antibody-dependent NK cell responses are induced by Plasmodium falciparum infected erythrocytes (iRBC) in peripheral blood mononuclear cells (PBMC) from malaria-exposed Gambian individuals in the presence of autologous sera, which are absent in those from malaria-naïve UK individuals. However, malaria hyper-immune serum promotes rapid NK cell responses to iRBC in cells from both Gambian and UK individuals. Among Gambians, highly differentiated, adaptive (CD56dimFcεR1γ-CD57+) NK cells dominate both antibody-dependent NK cell IFN-γ responses and degranulation responses, whereas among UK individuals these responses are predominantly found within canonical, highly differentiated CD56dimFcεR1γ+CD57+ NK cells. Indeed, overall frequencies of adaptive, FcεR1γ-CD57+ NK cells are significantly higher among Gambian donors compared to HCMV-infected and HCMV-uninfected UK adults. Among UK individuals, antibody-dependent NK cell IFN-γ responses to iRBC were dependent on IL-18 whereas among Gambians, the predominant adaptive FcεR1γ-NK cell response was IL-18 (and accessory cell) independent (although the lower frequency response of canonical FcεR1γ NK cells did rely on this cytokine).

Regulation of the human NK cell compartment by pathogens and vaccines

“…25 This is accompanied by loss of NK cell responsiveness to innate cytokines but maintenance of robust antibody-dependent activation 25 and emergence of high frequencies of 'adaptive' FceR1c À CD56 dim NK cells in childhood and early adulthood. 26,27 Similar effects are observed in temperate areas of the northern hemisphere, but over a more protracted period, with advanced NK cell differentiation mostly occurring later in life in these lower HCMV seroprevalence settings. [28][29][30]…”

“…in younger age groups) in settings of high HCMV endemicity with, for example, maximal expansion of CD57 + NKG2C + and CD57 + NKG2A + NK cells being reached by 10 years of age in an African population with near universal HCMV infection in the first year of life 25 . This is accompanied by loss of NK cell responsiveness to innate cytokines but maintenance of robust antibody‐dependent activation 25 and emergence of high frequencies of ‘adaptive’ FcεR1γ − CD56 dim NK cells in childhood and early adulthood 26,27 . Similar effects are observed in temperate areas of the northern hemisphere, but over a more protracted period, with advanced NK cell differentiation mostly occurring later in life in these lower HCMV seroprevalence settings 28–30 …”

“…There are also many examples of potent, Fc receptor‐mediated degranulation and cytokine production by more highly differentiated NK cells in response to vaccination‐induced antibody 76,94–96 . Moreover, subunit, virally vectored and whole viral vaccines, with or without chemical adjuvants, will provide distinct cytokine signatures for co‐stimulation of NK cell responses with type 1 interferons, IL‐15 and IL‐18, all described to support antibody‐dependent responses of adaptive NK cells 27,95,97,98 . However, it is not known whether these cytokine‐ and antibody‐mediated signals contribute to further differentiation of these particular NK cells.…”

Antibodies targeting merozoites induce natural killer cell degranulation and interferon gamma secretion and are associated with immunity against malaria

“…In malaria, natural killer cells were identified as part of the early innate immune response, through the production of IFNγ and soluble granzymes 14 . Although recent data suggest that they can acquire a memory-like “adaptive” phenotype following repeated exposure with malaria 17,46 , our study utilized malaria-naïve NK cells to interrogate their interaction with anti-merozoite antibodies. As shown for malaria antigens exposed on the surface of infected red cells 9,46,47 antibodies against merozoites induce Fc-receptor dependent NK activation.…”

Efferocytosis Mediated Modulation of Injury after Neonatal Brain Hypoxia-Ischemia

“…Efferocytosis represents a physiologic process of phagocytic clearance of AC from the tissue by phagocytic cells promoting the resolution of inflammation [ 1 ]. Efferocytosis is carried out by professional phagocytes [ 2 ], such as microglia, macrophages, neutrophils or dendritic cells.…”