Natural killer group 2 member D receptor ligands (NKG2DL)

NKG2D receptor ligands (NKG2DLs) are a group of cell surface proteins, including MICA, MICB, and the ULBP family, that are typically absent or lowly expressed on healthy cells but significantly upregulated in response to cellular stress, viral infection, or malignant transformation (Gasser et al., 2005; Raulet et al., 2013). These ligands serve as eat-me signals that are recognized by the activating receptor NKG2D, which is constitutively expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells (Groh et al., 1998). Upon binding, NKG2DLs trigger potent cytotoxic responses and cytokine production to eliminate the compromised cells. In the context of cancer, tumors often employ evasion strategies such as the proteolytic shedding of these ligands from the cell surface by metalloproteinases like ADAM17, creating soluble decoys that desensitize immune cells (Salih et al., 2002). Therapeutic strategies currently under investigation include monoclonal antibodies like CLN-619 that stabilize surface expression or prevent shedding, and CAR-T cells like CYAD-01 engineered with the NKG2D receptor to target ligand-expressing tumors (Cullinan Oncology; Celyad Oncology).

Other names

MHC class I polypeptide-related sequence AMHC class I polypeptide-related sequence BUL16-binding proteinsRAET1 proteinsStress-induced ligandsMICAMICBULBP1-6

Activation of the NKG2D receptor on natural killer (NK) cells and cytotoxic T cells to induce lysis of target cells; prevention of ligand shedding to maintain immune recognition.