The Impact of Glycosyl-Phosphatidyl-Inositol Anchored MICA Alleles on Novel NKG2D-Based Therapies

NKG2D is an activating receptor present in all human NK cells, CD8+ T cells, and in certain populations of CD4 T cells, and engagement of this receptor with its ligands is a crucial step in the regulation of both innate and specific immune responses [for review, see Ref. (1)]. NKG2D recognizes two families of MHC-related molecules, whose expression is, in general, upregulated when the cells suffer different types of stress including infection and tumorigenesis. In fact, a large variety of primary tumors and tumor-derived cell lines express NKG2D-ligands and, in the last few years, many reports have established correlations between the presence of NKG2Dligands in cancer patient serum and disease prognosis [for review, see Ref. (2)]. The presence of NKG2D-ligands in serum is related to another important feature of these molecules: they can be released to the supernatant by either metalloprotease cleavage or incorporated in nanovesicles (exosomes), depending on their biochemical features [for review, see Ref. (3)]. However, it is still not understood why NKG2D-ligands are, in some instances, secreted while in other cases they remain at the cell surface, and understanding the cellular “decisions” on the pathways followed by these molecules will be of crucial importance in the choice of novel therapies based on NKG2D, such as monoclonal antibodies or NKG2D-CARs [for review, see Ref. (4)], since soluble ligands could interfere with these therapies in different manners depending on their biological form. In this sense, detailed study of the differential features of each individual NKG2D-ligand is still needed and investigation of the mechanisms used by different viral gene products to interfere with NKG2D-ligand expression will likely be critical in uncovering these cell biology issues.