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

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 gamma delta T cells via TCR gamma delta. Here we show that immobilized soluble ULBP4 (rULBP4) induces the proliferation of human ovarian epithelial carcinoma- or colonic carcinoma-derived V delta 2(+) T cells in vitro. These V delta 2(+) 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 TCR gamma 9/delta 2 and activates TCR- Jurkat T cells transfected with TCR gamma 9/delta 2. Moreover, both TCR gamma delta and NKG2D are involved in ULBP4-induced activation and cytotoxicity of gamma delta T 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 TCR gamma delta and NKG2D and may play a key role in immune surveillance of tumor development and clearance of viral infection. (Blood. 2009; 114: 310-317)