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

Samuel Sherratt,Martin R Goodier,Eleanor M Riley,David A Baker,Avnish Patel

doi:10.3389/fimmu.2020.00533

Samuel Sherratt, Martin R Goodier + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2020.00533

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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).

Highlights

Natural killer cells integrate signals from both inflammatory mediators and acquired T and B cell responses, enabling them to bridge innate and adaptive immunity, the intrinsic differentiation state of these cells determines which combinations of signals contribute to their activation and function [1]
Our previous studies have demonstrated rapid differentiation of peripheral blood natural killer (NK) cells in Gambian children with frequencies and geometric mean fluorescence intensity (MFI) for the late differentiation marker CD57 stabilizing to levels reached in adult Gambians by the age of 14 years [31]
We observed low frequency but significant induction of IFN-γ in NK cells from Gambian donors in response to infected red blood cells (iRBC) compared to uninfected erythrocytes and these responses were further enhanced in the presence of autologous plasma (Figure 1A)

Summary

Introduction

Natural killer cells integrate signals from both inflammatory mediators and acquired T and B cell responses, enabling them to bridge innate and adaptive immunity, the intrinsic differentiation state of these cells determines which combinations of signals contribute to their activation and function [1]. Human cytomegalovirus infection is strongly associated with further diversification of the natural killer cell repertoire [4,5,6,7] including expansion of populations of CD57+NK cells bearing the c-type lectin-like receptor, NKG2C. This subset is highly represented amongst adaptive NK cells, which have lost expression of the proteomyeloid zinc finger (PLZF) molecule and the membrane adaptor protein FcεR1γ, switching to usage of components of the PI3 kinase signaling cascade including CD3ζ and ZAP70 and which can mount antibody dependent responses independently of cytokines [6, 7]. The expression of transcripts for IL-12 and IL-18 receptors and associated signaling components is lost in adaptive NK cells [7]

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