Abstract
Natural Killer (NK) cells are potent cytotoxic cells belonging to the family of Innate Lymphoid Cells (ILCs). Their most characterized effector functions are directed to the control of aberrant cells in the body, including both transformed and virus-infected cells. NK cell-mediated recognition of abnormal cells primarily occurs through receptor-ligand interactions, involving an array of inhibitory and activating NK receptors and different types of ligands expressed on target cells. While most of the receptors have become known over many years, their respective ligands were only defined later and their impressive complexity has only recently become evident. NKp44, a member of Natural Cytotoxicity Receptors (NCRs), is an activating receptor playing a crucial role in most functions exerted by activated NK cells and also by other NKp44+ immune cells. The large and heterogeneous panel of NKp44 ligands (NKp44L) now includes surface expressed glycoproteins and proteoglycans, nuclear proteins that can be exposed outside the cell, and molecules that can be either released in the extracellular space or carried in extracellular vesicles. Recent findings have extended our knowledge on the nature of NKp44L to soluble plasma glycoproteins, such as secreted growth factors or extracellular matrix (ECM)-derived glycoproteins. NKp44L are induced upon tumor transformation or viral infection but may also be expressed in normal cells and tissues. In addition, NKp44-NKp44L interactions are involved in the crosstalk between NK cells and different innate and adaptive immune cell types. NKp44 expression in different ILCs located in tissues further extends the potential role of NKp44-NKp44L interactions.
Highlights
Natural Killer (NK) cells are cytotoxic Innate Lymphoid Cells (ILCs) that patrol the body and play a crucial role in the defense against viruses and tumors by circulating in peripheral blood (PB) and extravasating into tissues, in particular at the sites of injury [1,2,3,4,5,6,7,8]
NKp44 engagement by Proliferating Cell Nuclear Antigen (PCNA) results in the inhibition of NK-mediated cytotoxicity and IFN-γ secretion by NK cells; this inhibitory effect is mediated by the Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) in NKp44 cytoplasmic tail and is observed only following an interaction with the ITIM-containing isoform NKp44-1, whose expression has been associated with poor survival in AML patients [36]
NKp44 has been shown to interact in cis with syndecan-4 (SDC4), one of the HSPGs expressed on the surface of NK cells, thereby constitutively dampening NKp44-mediated activation by preventing the receptor binding to other ligands expressed on target cells [60]
Summary
NK cells are cytotoxic Innate Lymphoid Cells (ILCs) that patrol the body and play a crucial role in the defense against viruses and tumors by circulating in peripheral blood (PB) and extravasating into tissues, in particular at the sites of injury [1,2,3,4,5,6,7,8]. NKp44 is implicated in the killing of virus-infected or tumor cells; the increasing panel of NKp44+ cells and the identification of new NKp44-ligands (NKp44L), possibly expressed in different tissues or released in the circulation, supports an important role for this receptor in tissue homeostasis and immune regulation [25,26,27,28,29]. In the tumor microenvironment, hypoxic conditions [42], or soluble mediators such as PGE2 [43,44,45] and TGF-β [46] can induce NK cells to down-regulate expression and/or function of major activating NK receptors including NKp44.
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