NKG2D ligand RAE1ε induces generation and enhances the inhibitor function of myeloid-derived suppressor cells in mice

Expression of surface NKG2D ligands on tumour cells, which activates nature killer (NK) cells and CD8(+) T cells, is crucial in antitumour immunity. Some types of tumours have evolved mechanisms to suppress NKG2D-mediated immune cell activation, such as tumour-derived soluble NKG2D ligands or sustained NKG2D ligands produced by tumours down-regulate the expression of NKG2D on NK cells and CD8(+) T cells. Here, we report that surface NKG2D ligand RAE1 epsilon on tumour cells induces CD11b(+)Gr-1(+) myeloid-derived suppressor cell (MDSC) via NKG2D in vitro and in vivo. MDSCs induced by RAE1 epsilon display a robust induction of IL-10 and arginase, and these MDSCs show greater suppressive activity by inhibiting antigen-non-specific CD8(+) T-cell proliferation. Consistently, upon adoptive transfer, MDSCs induced by RAE1 epsilon significantly promote CT26 tumour growth in IL-10- and arginase-dependent manners. RAE1 epsilon moves cytokine balance towards Th2 but not Th1 in vivo. Furthermore, RAE1 epsilon enhances inhibitory function of CT26-derived MDSCs and promotes IL-4 rather than IFN- production from CT26-derived MDSCs through NKG2D in vitro. Our study has demonstrated a novel mechanism for NKG2D ligand(+) tumour cells escaping from immunosurveillance by facilitating the proliferation and the inhibitory function of MDSCs.