Role of inositol phospholipid signaling in natural killer cell biology

Abstract

Natural killer (NK) cells are important for host defense against malignancy and infection. At a cellular level NK cells are activated when signals from activating receptors exceed signaling from inhibitory receptors. At a molecular level NK cells undergo an education process to both prevent autoimmunity and acquire lytic capacity. Mouse models have shown important roles for inositol phospholipid signaling in lymphocytes. NK cells from mice with deletion in different members of the inositol phospholipid signaling pathway exhibit defects in development, NK cell repertoire expression and effector function. Here we review the current state of knowledge concerning the function of inositol phospholipid signaling components in NK cell biology. Unlike T and B lymphocytes, natural killer (NK) cells do not rearrange antigen receptor genes in order to detect their cellular targets (Lanier, 1998). Rather, NK cells utilize an array of activating and inhibitory receptors with the latter largely detecting major histocompatibility complex (MHC) class I ligands, or in the case of 2B4, the signaling lymphocyte activation molecule (SLAM) family ligand CD48. Both activating and inhibitory NK receptors are stochastically expressed with frequencies in the NK compartment determined by their relative promoter strength, and in some cases, survival differences among NK subsets determined by the presence or absence of ligands their receptor array can detect and their relative affinity for that ligand (Manilay et al., 1999; Lowin-Kropf and Held, 2000; Wang et al., 2002; Fortenbery et al., 2010). Inhibitory receptors allow for the NK cell to recognize and ignore "healthy-self" cells while activating receptors enable the NK cell to recognize and lyse foreign or "damaged-self" cells or antibody bound cells. In some instances the NK cell may also produce inflammatory cytokines such as interferon (IFN)γ in response to target cell engagement (Vivier et al., 2011). Individual NK cells in the compartment can express different combinations of activating and inhibitory receptors, but also different levels of certain receptors (Bryceson et al., 2011). The final balance of activating and inhibitory receptors, and the presence or absence of ligands, determines a threshold for activation of an individual NK cell (Lanier, 1998; Bryceson et al., 2011; Vivier et al., 2011). In extreme cases the NK cell may even be anergized by unopposed activating signals (Raulet and Vance, 2006). This repertoire diversity in the NK cell compartment of an individual allows for a response to a diverse range of stimuli including an early response to virus-infected cells (Brandstadter and Yang, 2011) and surveillance for residual tumor cells (Vivier et al., 2008). Phosphatidylinositol (PI) is a membrane lipid found in all cell types that can be phosphorylated to form phosphatidylinositol 3-monophosphate PI(3)P, PI(4)P, or PI(5)P. Each of these PIP species can be further phosphorylated by phosphoinositide 3-kinase (PI3K), PI4K, or PI5K to form PIP2 species. PI3K is able to phosphorylate PI(4,5)P2 to form PI(3,4,5)P3 (Berridge and Irvine, 1989; Rhee and Bae, 1997). PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 allow for recruitment to the plasma membrane of pleckstrin homology (PH) domain-containing proteins (several other domains are also able to recruit proteins to these lipids as well and will be discussed below) as shown in Figure 1 and Table 1. PI(4,5)P2 is also important in NK cell signaling by acting as the substrate for phospholipase C (PLC), which hydrolyzes PI(4,5)P2 into diacylglycerol (DAG), to activate PKC and inositol 1,4,5-trisphosphate [I(1,4,5)P3] which triggers release of intracellular Ca2+ stores. PIP2 and PIP3 can be modified by various phosphatases including inositol polyphosphate 4-phosphatase (INPP4) and SH2 domain-containing inositol-5-phosphatase (SHIP) or modified by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) to create PI(3)P, PI(3,4)P2, or PI(4,5)P2, respectively. These activities can attenuate signaling pathways or, in the case of the SHIP product PI(3,4)P2, activate them by enabling recruitment of proteins with various PH domain-containing proteins to sites of signaling at the plasma membrane (Kerr, 2011). Here we will discuss the role of the above IP modifying enzymes in the context of NK cell biology. © 2013 Gumbleton and Kerr.