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

Killer cell lectin-like receptor subfamily K member 1 (NKG2D) is a type II transmembrane activating receptor expressed on NK cells, CD8+ T cells, and Cytokine-Induced Killer (CIK) cells (UniProt P26718). It serves as a critical component of the innate and adaptive immune systems by recognizing stress-induced ligands such as MICA, MICB, and ULBP1-6, which are typically upregulated on the surface of malignant or infected cells (PubMed: 23548215). In the specific context of CIK cell therapy, NKG2D acts as the primary trigger for non-MHC-restricted cytotoxicity, allowing these cells to target a broad range of tumors (PubMed: 31435310). Therapeutic strategies leveraging this interaction include NKG2D-based Chimeric Antigen Receptor (CAR) therapies, such as CYAD-01 and CYAD-101, which engineer immune cells to express the NKG2D extracellular domain (PubMed: 30206110). Additionally, bispecific antibodies and fusion proteins are being developed to enhance the recruitment of NKG2D-positive effectors to the tumor microenvironment (PubMed: 33613514). However, clinical efficacy can be compromised by the shedding of soluble NKG2D ligands by tumor cells, which acts as an immune evasion mechanism by desensitizing the receptor (PubMed: 29463564). Safety considerations include potential on-target, off-tumor toxicities due to low-level ligand expression in healthy tissues and the risk of cytokine release syndrome (PubMed: 30206110).

Other names

KLRK1CD314NK cell receptor DNatural killer group 2 member D

Activation of cytotoxic immune cells through DAP10-mediated signaling upon binding to stress-induced ligands (MICA/B, ULBPs) on target cells, leading to the release of perforin and granzymes (PubMed: 23548215).