The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/5/1451/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 9, May 3, 1999 1451-1460

Articles

Type I Interferons (IFNs) Regulate Tumor Necrosis Factor–related Apoptosis-inducing Ligand (TRAIL) Expression on Human T Cells: A Novel Mechanism for the Antitumor Effects of Type I IFNs

Nobuhiko Kayagaki*, Noriko Yamaguchi*,{ddagger}, Masafumi Nakayama*, Hiroshi Eto§, Ko Okumura*,{ddagger}, and Hideo Yagita*,{ddagger}

From the * Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; {ddagger} Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Chiyoda-ku, Tokyo 101-0062, Japan; and the § Department of Urology, Kobe University School of Medicine, Chuo-ku, Hyogo 650-0017, Japan

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a proapoptotic member of the TNF family of type II membrane proteins, which constitutes one component of T cell cytotoxicity. In this study, we investigated the expression and function of TRAIL in human peripheral blood T (PBT) cells. Although freshly isolated PBT cells did not express a detectable level of TRAIL on their surface, a remarkable TRAIL expression was rapidly induced on the surface of both CD4+ and CD8+ PBT cells upon stimulation with anti-CD3 monoclonal antibody and type I interferons (IFNs). This enhancement of TRAIL expression was a unique feature of type I IFNs (IFN-{alpha} and IFN-β), and neither type II IFN (IFN-{gamma}) nor various other cytokines enhanced TRAIL expression on anti-CD3–stimulated PBT cells. Type I IFNs have been used for clinical treatment of renal cell carcinomas (RCCs), and we found that most RCC cell lines were susceptible to TRAIL-induced apoptosis. Type I IFNs substantially augmented cytotoxic activity of anti-CD3–stimulated PBT cells against RCC cell lines in a TRAIL-dependent manner. These results indicate a unique feature of type I IFNs to regulate TRAIL-mediated T cell cytotoxicity, which may be involved in the antitumor effects of type I IFNs against various tumors.

Key Words: cytotoxic T lymphocyte • cytotoxicity • TRAIL • type I interferon • renal cell carcinoma

Address correspondence to Hideo Yagita, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: 81-3-3818-9284; Fax: 81-3-3813-0421; E-mail: hyagita{at}med.juntendo.ac.jp

Abbreviations used: CMA, concanamycin A; CML, chronic myelogenous leukemia; PBT, peripheral blood T; poly IC, polyinosinic acid:polycytidylic acid; RCC, renal cell carcinoma; STAT, signal transducer and activator of transcription; TIL, tumor-infiltrating T lymphocyte; TRAIL, TNF-related apoptosis-inducing ligand.


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