Modulation of signaling preference of NK cells by different forms of NKG2D ligands and its implications

Abstract

Abstract The significance of ligand-induced activation of NK cell activating receptor NKG2D has been well established in controlling tumor growth in various experimental animal models. Amongst different types of NKG2D ligands, MHC I chain related molecule MICA/B is expressed most prevalently in various human cancers. In particular, proteolytically shed form of MICA/B (sMIC) has been shown to suppress the immune system and found to correlate with advanced disease stages in cancer patients. Previous studies in our lab using two humanized bi-transgenic mice, one expressing native ligand (TRAMP/MICB) and the other expressing the shedding-resistant mutant (TRAMP/MICB.A2) revealed opposite roles of these ligands in regulating tumor immunity. MICB expressing mice exhibited increased tumor progression, whereas MICB.A2 expressing mice had tumor free survival. These findings raised the intriguing question of why do these structurally similar forms of MIC have vastly different effects on tumor immunity. To address this question, we investigated the signaling events and functional outcomes in NK cells upon stimulation by the two forms of ligands. In vitro co-culture studies of NK cells with tumor cell lines expressing sMICB and MICB.A2 revealed elevated pro-inflammatory and immunosuppressive cytokine production by NK cells upon stimulation with sMICB. In contrast, NK cells stimulated with MICB.A2 displayed enhanced expression of cytotoxicity mediators and signaling molecules of cytotoxicity pathway. This suggests that signaling through sMICB may polarize the NKG2D signaling pathways with preferential activation of inflammatory cytokine pathways. Our data has uncovered a new potential mechanism whereby sMIC promotes tumor progression.