NKG2D Receptor and Its Ligands in Host Defense

Abstract

NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, and subsets of CD4+ T cells, iNKT cells, and γδ T cells. In humans NKG2D transmits signals by its association with the DAP10 adapter subunit and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least 8 genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and post-translation. In general healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyper-proliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves a mechanism for the immune system to detect and eliminate cells that have undergone “stress”. Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases.

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…Thus, high levels of soluble NKG2D or DNAM-1 ligands were detected in serum of cancer patients and have been associated to advanced stages of the disease or to poor prognosis. 32,33,44 Increased amounts of soluble B7-H6 were found in sera of melanoma patients and in the peritoneal fluid of ovarian carcinoma patients. 47,49 Soluble BAG6/BAT3 was detected in sera of CLL patients and could modulate NKp30-mediated cytotoxicity.…”

“…32-34 Ligands specific for these receptors have been extensively characterized: MICA/B and ULBPs molecules are recognized by NKG2D, while PVR and Nectin-2 (belonging to the Nectin family), are ligands for DNAM-1. 32,33,35,36 …”

“…37-40 In this context, soluble ligands, endowed with suppressive capability, have been described for NKG2D and DNAM-1 activating receptors (sMICA, sULBPs, and sPVR) and for NKp30 (sB7H6 and sBAT3/BAG6). 32,33,35,41-50 On the other hand, extracellular ligands for NKp46 and NKp44 have been recently identified and demonstrated to have a positive effect on the NK cell function. NKp46 has been shown to bind an extracellular molecule: the Complement Factor P (CFP or properdin).…”

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

“…22,33 Cytokines such as IL-4 and TGF-β derived from the tumor microenvironment can down-regulate NKG2D expression on NK and CD8 + T cells and thereby dampen anti-tumor activit. 34–36 In contrast, cytokines that function through common γ chain receptors, including IL-2, IL-7, and IL-15, can support NKG2D expression on immune cell.…”

“…DAP10 contains a YxxM signaling motif, which may activate phosphatidylinositol 3-kinase-dependent signaling pathway. 21,22 Despite the roles of NKG2D and DAP10 signaling on T cells have been extensively studie, 23,24 the effect of DAP10 activation in the second-generation CAR-T cells, which generally utilize a CD28 or 4-1BB co-stimulatory domain, remains unknown. We hypothesized that DAP10 activation can improve the anti-tumor activity of second-generation CAR-T cells based on previous reports.…”