NKG2D ligands and adhesion molecules (NKG2DL/AM)

NKG2D ligands (NKG2DLs) and adhesion molecules are critical components of the immunological synapse that facilitate the recognition and elimination of stressed, infected, or malignant cells by the immune system (Schmiedel & Mandelboim, 2018, PMID: 29535734). NKG2DLs, which include MHC class I polypeptide-related sequences A and B (MICA/B) and UL16-binding proteins (ULBP1-6), are typically absent from the surface of healthy cells but are upregulated in response to cellular stressors such as DNA damage, viral infection, or oncogenic transformation (Dhar & Wu, 2018, PMID: 30108517). These ligands bind to the NKG2D activating receptor on Natural Killer (NK) cells and various T cell subsets, providing a potent signal for targeted cytotoxicity. Adhesion molecules, such as Intercellular Adhesion Molecule 1 (ICAM-1), complement this interaction by stabilizing the contact between the effector immune cell and the target cell, ensuring the efficient delivery of perforin and granzymes (Orange, 2008, PMID: 18437159). In the context of oncology, many tumors employ immune escape strategies by downregulating these surface molecules or shedding NKG2DLs into the systemic circulation as soluble decoys to desensitize immune cells (Zingoni et al., 2018, PMID: 29692772). Therapeutic strategies targeting this axis include NKG2D-based Chimeric Antigen Receptor (CAR) T-cell therapies, such as CYAD-01, which utilize the natural NKG2D receptor to recognize the broad array of ligands expressed on diverse tumor types. Additionally, monoclonal antibodies like 7C6 are being developed to prevent the proteolytic shedding of MICA/B, thereby maintaining high surface density for immune recognition and enhancing the anti-tumor response (Ferrari de Andrade et al., 2018, PMID: 29593293).

Other names

NKG2D ligandsStress-induced ligandsMHC class I polypeptide-related sequencesUL16-binding proteinsCell adhesion moleculesMICA/B and ULBPs

Activation of the NKG2D receptor on effector immune cells, such as Natural Killer (NK) cells and CD8+ T cells, to trigger cytotoxic granule release and cytokine production; stabilization of the immunological synapse via interactions between adhesion molecules (e.g., ICAM-1) and their receptors (e.g., LFA-1) to enhance effector-target cell binding and facilitate efficient cell lysis.