NKG2D Natural Killer Cell Receptor-A Short Description and Potential Clinical Applications

Abstract

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

Keywords: NK cells; NKG2D ligands; NKG2D receptor.

Figure 1

Activation of NKG2D-related pathways. NKG2D binding with its ligand activates several molecular pathways in NK cells, which is provided by the DAP10 signaling molecule. Cytotoxicity of NK cells may be activated through phospholipase C Gamma 2 (PLCγ2), c-Jun-NH (2)-terminal kinase (JNK) and phosphatidylinositol 3-hydroxy kinase PI3K. Granule release is activated by the PLCγ2 and PI3K pathways. The JAK-STAT5 (Janus kinase 2-Signal Transducer and Activator of Transcription 5) pathway results in cytokine release.

Figure 2

NKG2D association with NKG2DL’s triggers cytokine secretion by the NK cells (A). Malignant or virus-infected cells use soluble forms of NKG2DLs to decrease effectiveness of the NKG2D. ADAM protease molecules increase shedding of sNKG2DLs (B). In target therapy, NKG2D receptor is blocked by the anti-NKG2D monoclonal antibodies, which prevents it from binding with NKG2DLs (C).