Killer cell lectin-like receptor subfamily K member 1 and its ligands (MHC class I polypeptide-related sequence A, MHC class I polypeptide-related sequence B, and UL16-binding proteins 1-6) (NKG2D-NKG2DL axis)

The NKG2D receptor, encoded by the KLRK1 gene, is a pivotal activating receptor expressed on natural killer (NK) cells, CD8+ T cells, and certain gamma-delta T cell subsets. It recognizes a diverse array of stress-induced ligands, including MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence B (MICB), and the UL16-binding protein (ULBP) family (ULBP1-6). These ligands are typically absent from healthy tissues but are rapidly upregulated in response to cellular stressors such as DNA damage, viral infection, or malignant transformation, serving as a 'danger signal' for the immune system [1, 6]. Upon ligand binding, NKG2D triggers direct cytotoxicity and the production of pro-inflammatory cytokines like IFN-gamma, facilitating the elimination of compromised cells [4, 11]. In the context of oncology, many tumors evade this surveillance by shedding MICA/B into a soluble form, which can block the receptor or induce its internalization, leading to immune suppression [22, 25]. Conversely, in autoimmune conditions such as Crohn's disease and Celiac disease, the inappropriate activation of the NKG2D axis contributes to chronic inflammation and tissue damage [9, 35]. Therapeutic interventions currently under investigation include NKG2D-based CAR-T cells and bispecific antibodies for cancer, as well as receptor-blocking antibodies for inflammatory disorders [30, 33, 38].

Other names

CD314KLRK1Natural killer group 2 member DNKG2-DMHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6)Retinoic acid early transcript 1E (RAET1E)Retinoic acid early transcript 1G (RAET1G)Retinoic acid early transcript 1L (RAET1L)Retinoic acid early transcript 1H (RAET1H)Retinoic acid early transcript 1I (RAET1I)Retinoic acid early transcript 1N (RAET1N)

Drugs targeting the NKG2D-NKG2DL axis employ several mechanisms: (1) NKG2D-based CAR-T cells (e.g., CYAD-01) and bispecific engagers (e.g., NKG2D-CD3) directly target and lyse ligand-expressing tumor cells; (2) monoclonal antibodies (e.g., CLN-619, AHA-1031) bind to the alpha-3 domain of MICA/B to prevent proteolytic shedding, thereby stabilizing surface expression and enhancing NK cell-mediated ADCC; (3) blocking antibodies (e.g., NNC0142-0002) antagonize the NKG2D receptor to suppress overactive T cells in autoimmune diseases like Crohn's; and (4) small molecules like HDAC or proteasome inhibitors upregulate ligand expression on tumor cells to restore immune recognition [25, 30, 33, 38].