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Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8⁺ T Cells¹

Mika Kijima^2,*, Akiko Iwata^2,*,, Yoichi Maekawa^*, Hisanori Uehara, Keisuke Izumi, Akiko Kitamura^*, Hideo Yagita, Shigeru Chiba^¶, Hiroshi Shiota and Koji Yasutomo^3,*

^* Department of Immunology and Parasitology, Department of Ophthalmology and Visual Neuroscience, and Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and ^¶ Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4⁺ T cell proliferation and CII-specific Ab production. Depletion of either CD4⁺ or CD8⁺ T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4⁺ but not CD8⁺ T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8⁺ T cells, although Jagged1 could not directly inhibit CD8⁺ T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8⁺ T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8⁺ T cells in vivo, which suggests its therapeutic potential in the treatment of CD8⁺ T cell-mediated diseases, including rheumatoid arthritis.

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 work was supported by a Grant-in-Aid for Young Scientists (S) from the Japan Society for the Promotion of Science and a Grant-in-Aid for Scientific Research on Priority Areas from The Ministry of Education, Culture, Sports, Science and Technology.

² M.K. and A.I. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Koji Yasutomo, Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. E-mail address: yasutomo{at}basic.med.tokushima-u.ac.jp

⁴ Abbreviations used in this paper: DL, Delta-like; CIA, collagen-induced arthritis; CII, collagen type II; c-P, control plasmid; EAE, experimental autoimmune encephalomyelitis; sJag1-P, soluble Jagged1-encoding plasmid.