Killer cell lectin-like receptor subfamily K member 1 (NKG2D) (NKG2D)

Killer cell lectin-like receptor subfamily K member 1 (NKG2D) is a major activating receptor primarily expressed on natural killer (NK) cells and a co-stimulatory receptor on CD8+ T cells and γδ T cells [UniProt, PubMed]. It functions by recognizing a diverse set of stress-induced ligands, including MHC class I polypeptide-related sequence A (MICA), MICB, and UL16-binding proteins (ULBPs), which are upregulated on the surface of cells undergoing malignant transformation, viral infection, or DNA damage [NIH, PubMed]. Upon ligand binding, NKG2D signals through the adaptor protein DAP10 to trigger the release of cytotoxic granules and pro-inflammatory cytokines, facilitating the elimination of stressed or abnormal cells [Wikipedia, PubMed]. In the context of cancer, the NKG2D receptor–ligand axis is a key target for immunotherapy, with strategies including CAR-T/NK cells (e.g., CYAD-01), bispecific engagers, and drugs that upregulate ligand expression to overcome tumor immune escape mechanisms like ligand shedding [PMC, PubMed]. Conversely, in autoimmune diseases, the axis is targeted for inhibition to prevent the destruction of healthy tissues by overactive NK and T cells [Frontiers, PubMed].

Other names

KLRK1CD314NK cell receptor DNKG2-D-activating NK receptorKiller cell lectin-like receptor subfamily K member 1

Activation of NK cell and T cell cytotoxicity via NKG2D-DAP10 signaling; blockade of the NKG2D receptor to inhibit autoimmune responses; pharmacological upregulation of stress-induced ligands (MICA/B, ULBPs) on target cells; and prevention of ligand shedding to maintain immune recognition.