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 Blood, 9 July 2009, Vol. 114, No. 2, pp. 310-317.
Prepublished online as a Blood First Edition Paper on May 12, 2009; DOI 10.1182/blood-2008-12-196287.

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IMMUNOBIOLOGY

The NKG2D ligand ULBP4 binds to TCR{gamma}9/{delta}2 and induces cytotoxicity to tumor cells through both TCR{gamma}{delta} and NKG2D

Yan Kong1, Wei Cao1, Xueyan Xi1, Chi Ma1, Lianxian Cui1, and Wei He1

1 Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, National Key Laboratory of Medical Molecular Biology, Beijing, China

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.


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