Natural killer cell activating receptors (NKG2D and Natural Cytotoxicity Receptors) (NKG2D/NCRs)

NKG2D (Natural Killer Group 2 Member D) and Natural Cytotoxicity Receptors (NCRs), which include NKp30, NKp44, and NKp46, are primary activating receptors expressed on natural killer (NK) cells and specific subsets of T cells (UniProt: P26718, O76036). These receptors are essential for the immune system's ability to detect and eliminate abnormal cells, as they recognize a variety of ligands that are typically absent on healthy cells but upregulated during cellular stress, viral infection, or malignant transformation (PubMed: 11491509). NKG2D specifically binds to stress-induced proteins such as MICA, MICB, and the ULBP family, while NCRs recognize ligands like B7-H6 and various viral hemagglutinins (PubMed: 21734677). In oncology, these receptors are major targets for immunotherapy, including the development of bispecific NK-cell engagers (BiKEs) and CAR-NK cell therapies designed to bypass tumor-induced immunosuppression. By triggering these receptors, therapeutic agents can potently induce the release of perforin and granzymes, leading to the direct lysis of tumor cells. However, challenges remain regarding the shedding of soluble ligands by tumors, which can act as decoys and downregulate receptor expression on effector cells (PubMed: 29961571).

Other names

NK cell activating receptorsKLRK1NCR1NCR2NCR3NKp46NKp44NKp30Natural killer group 2 member D

Activation of natural killer (NK) cells and cytotoxic T cells through receptor engagement to induce apoptosis and lysis of tumor cells expressing stress-induced or pathogen-derived ligands.