The NKG2D ligand ULBP4 binds to TCRγ9/δ2 and induces cytotoxicity to tumor cells through both TCRγδ and NKG2D

Abstract

Abstract UL16-binding proteins (ULBPs) belong to a family of ligands for NKG2D activating receptor of human natural killer (NK) cells. We previously reported that RAET1E2, a soluble isoform of the RAET1E (ULBP4), inhibits NKG2D-mediated NK cytotoxicity. In this study, we examined whether ULBP4 could be recognized by γδT cells via TCRγδ. Here we show that immobilized soluble ULBP4 (rULBP4) induces the proliferation of human ovarian epithelial carcinoma– or colonic carcinoma–derived Vδ2+ T cells in vitro. These Vδ2+ T cells secrete Th1 cytokines and display a strong cytolytic activity toward ULBP4-transfected targets. We also show that ULBP4 binds to a soluble chimeric protein containing TCRγ9/δ2 and activates TCR− Jurkat T cells transfected with TCRγ9/δ2. Moreover, both TCRγδ and NKG2D are involved in ULBP4-induced activation and cytotoxicity of γδT cells. We found that ULBP4 is expressed not only on human tumor cells, but also on Epstein-Barr virus (EBV)–infected peripheral blood cells. Taken together, our data suggest that ULBP4 functions as a ligand for both TCRγδ and NKG2D and may play a key role in immune surveillance of tumor development and clearance of viral infection.