Regulation of NK Cell Activation and Effector Functions by the IL-12 Family of Cytokines: The Case of IL-27

Norberto Walter Zwirner,Andrea Ziblat

doi:10.3389/fimmu.2017.00025

Abstract

Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by secretion of immunoregulatory cytokines such as IFN-γ. Activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and because of a bidirectional cross talk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23, and IL-27 and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15, and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human) remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. Recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN-γ secretion, NKp46-dependent NK cell-mediated cytotoxicity, and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions.

Highlights

Natural killer (NK) cells constitute one of the three major lymphoid cell populations in blood
A kinetic analysis of the production of these cytokines needs to be performed to establish the temporal relationship in their secretion, the cooperation between IL-27 and IL-18 that we described unravels the existence of a hierarchical cytokine network that is relevant during dendritic cells (DC)-NK cell cross talk that generates fully functional NK cells
Natural killer cells are currently viewed as cytotoxic cells and as strong producers of immunoregulatory cytokines, in particular, IFN-γ. They belong to the family of immune lymphoid cell populations (ILC), and their effector functions are tightly regulated by interaction with DC and other cells of myeloid lineage, which secrete cytokines with NK cell-stimulating activity

Summary

INTRODUCTION

Natural killer (NK) cells constitute one of the three major lymphoid cell populations in blood. Human NK cells express functional TLR3, TLR7, and TLR9, and stimulation of NK cells with their agonists triggers IFN-γ secretion only in the presence of suboptimal concentrations of IL-12 or IFN-α but not IL-15 [25] This effect was further potentiated by co-engagement of NKG2D, one of the major cell surface receptors involved in recognition and elimination of tumor cells by NK cells, but TLR agonists do not seem to exert immunoregulatory effects on NKG2D-dependent NK cell-mediated cytotoxicity [5]. The focus of our laboratory has been the investigation of how NK cells sense their environment and unravel novel factors that affect their phenotype and functions

REGULATION OF NK CELL ACTIVATION

CONCLUDING REMARKS