Identification and Molecular Characterization of Nkp30, a Novel Triggering Receptor Involved in Natural Cytotoxicity Mediated by Human Natural Killer Cells

TLDR

Human natural cytotoxicity is mediated by the receptors NKp46 and NKp44, but evidence suggests additional receptors exist. The study aimed to identify additional NK cell triggering receptors. The authors generated monoclonal antibodies and discovered NKp30, a 30‑kD receptor expressed on all resting and activated NK cells. Cross‑linking NKp30 activates NK cells, whereas masking inhibits cytotoxicity, NKp30 cooperates with NKp46/NKp44 for most targets and is the primary trigger for certain tumors, associates with tyrosine‑phosphorylated CD3ζ, and is encoded by the 1C7 gene, a member of the immunoglobulin superfamily with a single V‑type domain and a charged transmembrane residue.

Abstract

Two major receptors involved in human natural cytotoxicity, NKp46 and NKp44, have recently been identified. However, experimental evidence suggested the existence of additional such receptor(s). In this study, by the generation of monoclonal antibodies (mAbs), we identified NKp30, a novel 30-kD triggering receptor selectively expressed by all resting and activated human natural killer (NK) cells. Although mAb-mediated cross-linking of NKp30 induces strong NK cell activation, mAb-mediated masking inhibits the NK cytotoxicity against normal or tumor target cells. NKp30 cooperates with NKp46 and/or NKp44 in the induction of NK-mediated cytotoxicity against the majority of target cells, whereas it represents the major triggering receptor in the killing of certain tumors. This novel receptor is associated with CD3ζ chains that become tyrosine phosphorylated upon sodium pervanadate treatment of NK cells. Molecular cloning of NKp30 cDNA revealed a member of the immunoglobulin superfamily, characterized by a single V-type domain and a charged residue in the transmembrane portion. Moreover, we show that NKp30 is encoded by the previously identified 1C7 gene, for which the function and the cellular distribution of the putative product were not identified in previous studies.