Generation of Soluble NKG2D Ligands: Proteolytic Cleavage, Exosome Secretion and Functional Implications

Abstract

The activating natural killer group 2 member D (NKG2D) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG2D comprise two groups of MHC class I-related molecules, the MHC class I chain-related proteins A and B (MICA/B) and 6 UL16-binding proteins (ULBP1-6). While NKG2D 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 NKG2D ligand and thereby are susceptible to NKG2D-dependent immunosurveillance. However, soluble NKG2D ligands are released from tumour cells and can down-modulate NKG2D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG2D ligands in the serum correlate with tumour progression. NKG2D 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, NKG2D 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 NKG2D ligands can exert multiple effects on NKG2D/NKG2D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG2D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome-secreted NKG2D ligands for immunosurveillance.

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…In humans, six ligands for NKG2D have been identified: MHC class I-related chains A and B (MICA and B) and four ULBP molecules (Bauer et al, 1999;Groh et al, 2001). NKG2D ligands are barely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cells or infected cells (Chitadze et al, 2013;Nausch and Cerwenka, 2008).…”

Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model

“…NKG2D-mediated recognition of MICA/B molecules markedly costimulates TCR-dependent effector responses of Vδ2 + T cells, and may also be sufficient to activate them in a TCRindependent manner (21)(22)(23). However, ligands recognized by NKG2D can be downregulated from the cell surface by tumor cells and secreted in a soluble form as a mechanism of immune evasion or suppression (24), and therefore the use of this recognition pathway for immunotherapy must be carefully evaluated.…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…Shedding of MIC molecules primarily depends on a proteolytic process involving multiple enzymes, including a disintegrin and metalloproteinase (ADAM)9, ADAM10, ADAM17, some members of the matrix metalloproteinases (MMP) family (MMP9 and MMP14), and the disulfide isomerase Erp5 (13). Another level of complexity is reflected by the fact that MICA displays a high degree of polymorphism leading to an allele-dependent shedding, as demonstrated for the allelic variant MICA*008 released in association with exosomes (14).…”