Natural killer group 2 member D (NKG2D) (NKG2D)

Natural killer group 2 member D (NKG2D) is a major activating receptor found on natural killer (NK) cells, CD8+ T cells, and certain subsets of γδ T cells [1]. It functions as a molecular sensor for induced-self by recognizing stress-induced ligands, such as MICA, MICB, and ULBP proteins, which are typically absent on healthy cells but highly expressed on tumor cells and virally infected cells [2]. Upon ligand binding, NKG2D triggers potent cytotoxic responses and cytokine production to eliminate the target cell [3]. In oncology, this axis is a significant focus for immunotherapy, with strategies including CAR-T and CAR-NK cells engineered with NKG2D, as well as antibodies designed to prevent the shedding of ligands that tumors use to evade immune detection [4]. Despite its therapeutic potential, challenges include the risk of off-tumor toxicity if ligands are expressed on non-malignant stressed tissues and the systemic immunosuppression caused by soluble ligands in the tumor microenvironment [2,3].

Other names

KLRK1CD314Killer cell lectin-like receptor subfamily K member 1NKG2-D type II integral membrane proteinNKG2D-MICA/B axis

Activation of NK cells and cytotoxic T cells through binding to stress-induced ligands (MICA, MICB, ULBPs) on the surface of transformed or infected cells, leading to targeted cell lysis.