Human NK cells, their receptors and function

Abstract

NK cells are cytotoxic components of innate lymphoid cells (ILC) that provide a first line of defense against viral infections and contribute to control tumor growth and metastasis. Their function is finely regulated by an array of HLA-specific and non-HLA-specific inhibitory and activating receptors which allow to discriminate between healthy and altered cells. Human NK cells gained a major attention in recent years because of the important progresses in understanding their biology and of some promising data in tumor therapy. In this review, we will outline well-established issues of human NK cells and discuss some of the open questions, debates, and recent advances regarding their origin, differentiation, and tissue distribution. Newly defined NK cell specializations, including the impact of inhibitory checkpoints on their function, their crosstalk with other cell types, and the remarkable adaptive features acquired in response to certain virus infections will also be discussed.

Keywords: Adaptive NK cells; Human NK cells; Inhibitory checkpoints; NK cell receptors; TLR.

Figure 1

Model of “branched” NK cell development. Starting from HSC in the BM (CD34⁺ cells), NK cell development proceeds by steps, each characterized by a peculiar surface phenotype reported for each stage. The linear pathway has been characterized in SLTs and goes through stage 2 (CD34⁺CD117⁺ cells), stage 3 (CD34^–CD117⁺ cells), stage 4 (CD94⁺CD16⁻CD56^bright NK cells), stage 5 (CD16⁺KIR⁺CD56^dim NK cells), and stage 6 (the CD56^dimCD57⁺ terminally differentiated NK cells). In addition, HSC can generate CD117⁺ ILCP that are localized in PB and peripheral tissues and are analogous to stage 3 NK cells in SLT. ILCPs generate NK cells and helper ILCs. Moreover, in vitro and in humanized mice a myeloid precursor has been identified (CD33⁺CD56⁺), which also generates NK cells. Finally, it was reported that a lymphoid precursor characterized by a CD34⁺DNAM1^brightCXCR4⁺ phenotype residing in the BM is mobilized in the PB in chronic inflammation and is able to generate NK cells and α/β‐T cells, as well as mature NKG2C⁺CD57⁺ “adaptive” NK cells.

Figure 2

Fine regulation of NK cell function by inhibitory and activating interactions. (A) NK cells are tolerant towards healthy cells, expressing normal levels of ligands (i.e. high HLA class I molecules and low activating ligands), and, thus, inhibitory signals through HLA‐specific inhibitory receptors (KIRs and NKG2A) block activation. The weight of inhibition exceeds activation. (B and C) NK cells can kill pathological (e.g. tumor transformed or virally infected) cells, characterized by overexpression of stress‐inducible ligands (B, “Induced self‐recognition”), increasing the strength of activating interactions, and/or by downregulation of HLA class I expression (C, “Missing self‐recognition”), reducing/abrogating the inhibition mediated by HLA‐specific inhibitory receptors. In both instances, the “on” signal prevails.

Figure 3

Activating and inhibitory NK receptors and their ligands. (A) NK cells express an array of non‐HLA class I‐ specific activating and inhibitory receptors that recognize ligands usually expressed at the surface of target cells. Certain ligands can also be enzymatically shed and released as soluble ligands, such as B7‐H6, CD155, MICA, MICB, ULBPs, or can be secreted from intracellular compartments, such as BAT3, while further ligands are components of the ECM, such as Nidogen‐1 (Nid‐1) and collagen. PS, phosphatidylserine, PE, phosphatidylethanolamine; HA, hemagglutinin. (B) Different HLA class I‐specific inhibitory and activating receptors are expressed by NK cells that can recognize nonclassical HLA class I molecules (e.g. HLA‐E, HLA‐G, HLA‐F) or epitopes shared by distinct groups of HLA‐A, ‐B, or ‐C allotypes (i.e. C1, C2, and Bw4). The ligands of some HLA class I‐specific receptors are still unknown (e.g. KIR2DS3, KIR2DL5). The receptor KIR2DL4 (in purple) can deliver both inhibitory and activating signals. For details on KIRs and their ligands, see Ref. [53]. Inhibitory receptors are depicted in red and activating receptors are depicted in blue in both panels.