NKp44-NKp44 Ligand Interactions in the Regulation of Natural Killer Cells and Other Innate Lymphoid Cells in Humans

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.

Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential

“…Upon ligand binding, NKp44 interacts with a dimer of immunoreceptor tyrosine‐based activation motif (ITAM) of the adaptor DNAX‐activating protein 12 (DAP12/KARAP/Tyrobp), via the positively charged lysine in the transmembrane region, to transmit an activating signal . NKp44 signaling is important for potentiating NK cell cytotoxicity against tumor cells and the recognition and lysis of virus‐infected cells . NKp44 expression has also been documented in other immune cells, including plasmacytoid dendritic cells , cytotoxic ILC1s and a subset of ILC3s , potentially conferring NK‐like signaling programs to these cells .…”

Recalling the Biological Significance of Immune Checkpoints on NK Cells: A Chance to Overcome LAG3, PD1, and CTLA4 Inhibitory Pathways by Adoptive NK Cell Transfer?

“…The only activating receptor that has not been found in nonactivated NK cells is NKp44 that is rapidly upregulated after in vitro cytokine-mediated activation (26). Although NKp44 has been found to be constitutively expressed in a tissue-specific fashion on type 3 innate lymphoid cells and a subset of DCs (27), the role of this receptor in tumor immunosurveillance is not clear since it has not been detected yet in circulating or tumor infiltrated NK cells in vivo. Thus, in contrast to most NK cell-ICs and activating receptors, NKp44 has not been tested yet as a candidate for immunotherapy (28).…”

Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer

“…NCR2 can be expressed as three splice variants. Transcripts-2 and -3 bear a short intracellular tail while the longer endodomain of transcript-1 contains an ITIM, potentially enabling this isoform to relay both activating and inhibitory signals [29,[116][117][118]. The tumour cytokine milieu and hypoxic microenvironment has also been reported to influence cell surface expression and the activating or inhibitory outcome of NKp44 signalling [116].…”

“…Transcripts-2 and -3 bear a short intracellular tail while the longer endodomain of transcript-1 contains an ITIM, potentially enabling this isoform to relay both activating and inhibitory signals [29,[116][117][118]. The tumour cytokine milieu and hypoxic microenvironment has also been reported to influence cell surface expression and the activating or inhibitory outcome of NKp44 signalling [116]. An NKp44 ligand was first identified on human immunodeficiency virus-1-infected CD4 + T cells, subsequently characterized as an isoform of mixedlineage leukaemia protein 5 (MLL5), a predominantly nuclear protein that regulates the cell cycle [119].…”