Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin

Abstract

NKG2D is a recently described activating receptor expressed by both NK cells and CTL. In this study we investigated the role of NKG2D in the natural cytolysis mediated by NK cell clones. The role of NKG2D varied depending on the type of target cells analyzed. Lysis of various tumors appeared to be exclusively natural cytotoxicity receptors (NCR) dependent. In contrast, killing of another group of target cells, including not only the epithelial cell lines HELA and IGROV-1, but also the FO-1 melanoma, the JA3 leukemia, the Daudi Burkitt lymphoma and even normal PHA-induced lymphoblasts, involved both NCR and NKG2D. Notably, NK cell clones expressing low surface densities of NCR (NCR(dull)) could lyse these tumors in an exclusively NKG2D-dependent fashion. Remarkably, not all of these targets expressed MICA/B, thus implying the existence of additional ligands recognized by NKG2D, possibly represented by GPI-linked molecules. Finally, we show that the engagement of different HLA class I-specific inhibitory receptors by either specific antibodies or the appropriate HLA class I ligand led to inhibition of NKG2D-mediated NK cell triggering.

Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients

“…As NKG2D is a relatively new NK cell receptor most of the existing reports deal with basic data pertaining to its structure and function in rodent and human NK cells and lines [4,33], as well as with its putative ligands in animal tumors or characterized cell lines [34,35]. However, aside from individual reports, such as the one dealing with its expression in a T cell subset [36], there are scarce reports of its expression in any innate immunity cell subpopulation in cancer patient.…”

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

“…Its function requires the association with a newly identified signaling subunit termed DAP10 16 or KAP10 17. As recently shown, NKG2D can complement the role of NCRs in tumor cell lysis, their relative involvement being primarily dependent on the type of target and/or effector cells analyzed 15.…”

“…Upon recognition of the stress-inducible MICA/B molecules 14 on target cells, NKG2D strongly enhances the NK-mediated cytotoxicity 14 15. Different from NCR, NKG2D is also expressed by virtually all TCR-γ/δ + as well as by CD8 + TCR-α/β + cells.…”

Surface receptors and functional interactions of human natural killer cells: from bench to the clinic

“…An additional receptor, NKG2D, is present in both NK cells and cytotoxic T lymphocytes (CTLs). NKG2D is specific for the stress-inducible MICA/B [25,26] or for ULBP proteins [27,28]. Remarkably, MICA/B are expressed predominantly, but not exclusively, by cells of epithelial origin.…”

“…Remarkably, MICA/B are expressed predominantly, but not exclusively, by cells of epithelial origin. NKG2D is involved in NK-mediated cytotoxicity against certain tumors that express at least one of the above ligands [26,28]. In contrast, the cellular ligands recognized by NCR have not been identified so far; however, the available information is compatible with the concept that these ligands may also be expressed primarily by activated or proliferating cells.…”