Developmental and Functional Control of Natural Killer Cells by Cytokines

Abstract

Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.

CD83+CCR7+ NK cells induced by interleukin 18 by dendritic cells promote experimental autoimmune uveitis

“…IL‐18 involves binding with its receptor, consisting of IL‐18R1 and IL‐18R accessory protein in a heterodimeric receptor complex, to initiate signal transduction by the myeloid differentiation primary response protein 88 (MyD88). The nuclear factor (NF) kappa‐light‐chain‐enhancer of activated B cells (κB) and mitogen‐activated protein kinase pathways (MAPK pathways) are then activated, which promote IFN‐γ transcription and stabilization of IFNG mRNA . Recently, the role of IL‐18 in uveitis has attracted considerable attention as it has been shown in both clinical and EAU models, that IL‐18 shows enhanced expression during the inflammatory phase of the disease, and polymorphism of the IL‐18 gene is closely related to the occurrence of uveitis .…”

Concomitant deletion of SLAM-family receptors, NKG2D and DNAM-1 reveals gene redundancy of NK cell activating receptors in NK cell development and education

“…NK cell development is mainly regulated by cytokine signaling, in particular, in IL‐15 signaling . In this study, we reveal the synergistic role of multiple NK cell activating receptors in NK cell differentiation.…”

“…Sequential acquisition of a series of NK cell activating receptors occurs during the early stages of NK cell differentiation, usually preceding the expression of MHC‐I‐specific inhibitory receptors . Although IL‐15 signaling is indispensable for NK cell lineage commitment and differentiation, NK cell activating receptors, in particular SFRs and NKG2D, are also involved in this process . Deficiency of either SFRs or NKG2D caused subtle alterations in NK cell differentiation .…”

Natural killer cells are pivotal for in vivo protection following systemic infection by Sporothrix schenckii

“…CD11b + CD27 À NK cells have been reported to show increased expression of CD62L, S1P 5 (sphingosine-1-phosphate receptor 5), CX 3 CR1, CXCR3, CXCR4 and CCR1. [6][7][8][9] Although both CD25 and CD69 were found only at steady-state levels in S. schenckii-infected mice, KLRG1 had its expression up-regulated more than twofold. Additionally, CX 3 CR1 is highly expressed and mainly found on KLRG1 + NK cells (considered fully mature CD11b + CD27 À cells) identifying an even later maturation stage shown to have impaired IFN-c production and cytotoxicity towards YAC-1 cells under cytokine stimulation.…”

“…1,2 NK cell development from the earliest NK cell-committed precursor to functionally competent mature NK cells is a stepwise process that involves the sequential acquisition of a series of surface molecules. [6][7][8][9] However, our current understanding of NK cell biology in disease conditions comes almost entirely from the setting of tumours and viral infections, with data on NK cell modulation by fungal infections being preliminary at best. Additionally, murine NK cells can be further dissected into four distinct maturation stages defined by the differential surface expression of CD11b (a M integrin) and CD27 [a tumour necrosis factor (TNF) receptor family member], from the least to the most mature, as follow: CD11b À CD27 À ?…”