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Galectin-9 Increases Tim-3⁺ Dendritic Cells and CD8⁺ T Cells and Enhances Antitumor Immunity via Galectin-9-Tim-3 Interactions¹

Keiko Nagahara^2,*,, Tomohiro Arikawa^2,*, Souichi Oomizu^2,*, Keiichi Kontani, Atsuya Nobumoto^*,¶, Hiroaki Tateno^||, Kota Watanabe^¶, Toshiro Niki^¶, Shigeki Katoh, Minoru Miyake, Syun-Ichiro Nagahata, Jun Hirabayashi^||, Vijay K. Kuchroo^#, Akira Yamauchi and Mitsuomi Hirashima^3,*

^* Department of Immunology and Immunopathology, Department of Oral and Maxillofacial Surgery, Department of Respiratory, Breast, and Endocrine Surgery, and Cell Regulation, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan; ^¶ Research Center, Galpharma Company, Takamatsu, Kagawa, Japan; ^|| Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan; ^# Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

A Tim-3 ligand, galectin-9 (Gal-9), modulates various functions of innate and adaptive immune responses. In this study, we demonstrate that Gal-9 prolongs the survival of Meth-A tumor-bearing mice in a dose- and time-dependent manner. Although Gal-9 did not prolong the survival of tumor-bearing nude mice, transfer of naive spleen cells restored a prolonged Gal-9-induced survival in nude mice, indicating possible involvement of T cell-mediated immune responses in Gal-9-mediated antitumor activity. Gal-9 administration increased the number of IFN--producing Tim-3⁺ CD8⁺ T cells with enhanced granzyme B and perforin expression, although it induced CD4⁺ T cell apoptosis. It simultaneously increased the number of Tim-3⁺CD86⁺ mature dendritic cells (DCs) in vivo and in vitro. Coculture of CD8⁺ T cells with DCs from Gal-9-treated mice increased the number of IFN- producing cells and IFN- production. Depletion of Tim-3⁺ DCs from DCs of Gal-9-treated tumor-bearing mice decreased the number of IFN--producing CD8⁺ T cells. Such DC activity was significantly abrogated by Tim-3-Ig, suggesting that Gal-9 potentiates CD8⁺ T cell-mediated antitumor immunity via Gal-9-Tim-3 interactions between DCs and CD8⁺ T cells.

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 a grant from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

² K.N., T.A., and S.O. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Mitsuomi Hirashima, Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, 1750- 1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0791, Japan. E-mail address: mitsuomi{at}kms.ac.jp

⁴ Abbreviations used in this paper: Gal-9, Galectin-9; CRD, carbohydrate recognition domain; DC, dendritic cell; iDC, immature DC; mDC, mature dendritic cell; mIL-2, murine IL-2; MSC, myeloid-derived suppressor cell; PEC, peritoneal exudate cell; PI, propidium iodide; poly-LN, polylactosamine; Tim, T cell Ig- and mucin domain-containing molecule; Treg, regulatory T cell.

⁵ The online version of this article contains supplemental material.