Generation of Soluble NKG 2 D Ligands: Proteolytic Cleavage, Exosome Secretion and Functional Implications

The activating natural killer group 2 member D ( NKG 2 D ) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG 2 D comprise two groups of MHC class I‐related molecules, the MHC class I chain‐related proteins A and B ( MICA /B) and 6 UL 16‐binding proteins ( ULBP 1‐6). While NKG 2 D ligands are absent from most normal cells, expression is induced upon stress and malignant transformation. In fact, most solid tumours and leukaemia/lymphomas constitutively express at least one NKG 2 D ligand and thereby are susceptible to NKG 2 D ‐dependent immunosurveillance. However, soluble NKG 2 D ligands are released from tumour cells and can down‐modulate NKG 2 D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG 2 D ligands in the serum correlate with tumour progression. NKG 2 D ligands can be proteolytically shed from the cell surface or liberated from the membrane by phospholipase C in the case of glycosylphosphatidylinositol ( GPI )‐anchored molecules. Moreover, NKG 2 D ligands can be secreted in exosomal microvesicles together with other tumour‐derived molecules. Depending on the specific tumour/immune cell setting, these various forms of soluble and/or exosome‐bound NKG 2 D ligands can exert multiple effects on NKG 2 D / NKG 2 D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG 2 D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome‐secreted NKG 2 D ligands for immunosurveillance.