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Preferential Involvement of Tim-3 in the Regulation of Hepatic CD8⁺ T Cells in Murine Acute Graft-versus-Host Disease¹

Tsunekazu Oikawa^*,, Yosuke Kamimura^*, Hisaya Akiba, Hideo Yagita, Ko Okumura, Hiroki Takahashi, Mikio Zeniya, Hisao Tajiri and Miyuki Azuma^2,*

^* Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Medical School, Tokyo, Japan; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Tim-3, a member of the T cell Ig mucin (TIM) family regulates effector Th1 responses. We examined Tim-3 and its ligand expression as well as the effects of anti-Tim-3 mAb treatment in a murine model of acute graft-vs-host disease (aGVHD). In mice with aGVHD, Tim-3 expression was markedly up-regulated on splenic and hepatic CD4⁺ and CD8⁺ T cells, dendritic cells (DCs), and macrophages, and this was especially dramatic in hepatic CD8⁺ T cells. Both donor- and host-derived CD8⁺ T cells induced similar levels of Tim-3. Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes. The administration of anti-Tim-3 mAbs accelerated aGVHD, as demonstrated by body weight loss, reduction in total splenocyte number, and infiltration of lymphocytes in the liver. IFN- expression by splenic and hepatic CD4⁺ and CD8⁺ T cells was significantly augmented by anti-Tim-3 mAb treatment. In addition, the cytotoxicity against host alloantigen by donor CD8⁺ T cells was enhanced. These results demonstrate that the anti-Tim-3 treatment in aGVHD augmented the activation of effector T cells expressing IFN- or exerting cytotoxicity. Our results suggest that Tim-3 may play a crucial role in the regulation of CD8⁺ T cells responsible for the maintenance of hepatic homeostasis and tolerance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Miyuki Azuma, Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. E-mail address: miyuki.mim{at}tmd.ac.jp

³ Abbreviations used in this paper: Tim-3L, Tim-3 ligand; aGVHD, acute graft-versus-host disease; CHO, Chinese hamster ovary; HMC, hepatic mononuclear cell; DC, dendritic cell.

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