Natural killer group 2 member D ligands (NKG2DL)

NKG2D ligands (NKG2DLs) are a group of MHC class I-related surface glycoproteins, including MICA, MICB, and the ULBP family (ULBP1-6), that are upregulated on cells experiencing physiological stress such as malignancy, infection, or DNA damage [1][2]. These ligands act as critical recognition signals for the NKG2D (KLRK1) activating receptor, which is constitutively expressed on Natural Killer (NK) cells and γδ T cells, and inducible on CD8+ T cells and Cytokine-Induced Killer (CIK) cells [3][4]. Binding of NKG2DLs to the receptor triggers a potent signaling cascade leading to the release of perforin and granzymes, resulting in the cytolysis of the target cell [2]. In many cancers, tumor cells attempt to evade this immune surveillance by shedding these ligands from their surface via metalloproteinases, creating soluble decoys that inhibit immune function [5]. Therapeutic approaches currently in development include NKG2D-based Chimeric Antigen Receptor (CAR) T-cell therapies and bispecific antibodies that leverage this stress-sensing pathway to direct immune effectors against a wide variety of solid and hematological tumors [1][6]. Sources: [1] Schmiedel, V. M., & Mandelboim, O. (2018). NKG2D ligands—proteolytic shedding and its role in cancer immune escape. Frontiers in Immunology. [2] Lanier, L. L. (2015). NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunology Research. [3] Sangiolo, D. (2011). Cytokine-induced killer cells as adoptive immunotherapy for cancer: current status and future perspectives. Autoimmunity Reviews. [4] Silva-Santos, B., et al. (2015). γδ T cells in cancer: the role of NKG2D. Nature Reviews Immunology. [5] Waldhauer, I., & Steinle, A. (2008). NK cells and cancer immunosurveillance. Oncogene. [6] Baumeister, S. H., et al. (2019). Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Cancer Immunology Research.

Other names

MHC class I polypeptide-related sequence AMHC class I polypeptide-related sequence BUL16-binding proteinsMICAMICBULBP1ULBP2ULBP3ULBP4ULBP5ULBP6RAET1 proteinsStress-induced ligands

Activation of the NKG2D receptor on effector lymphocytes (NK cells, γδ T cells, and CD8+ T cells) to induce targeted lysis of ligand-expressing cells and stimulate proinflammatory cytokine production.