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Involvement of Regulatory T Cells in the Experimental Autoimmune Encephalomyelitis-Preventive Effect of Dendritic Cells Expressing Myelin Oligodendrocyte Glycoprotein plus TRAIL¹

Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

We previously reported the protection from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) by the adoptive transfer of genetically modified embryonic stem cell-derived dendritic cells (ES-DC) presenting MOG peptide in the context of MHC class II molecules and simultaneously expressing TRAIL (ES-DC-TRAIL/MOG). In the present study, we found the severity of EAE induced by another myelin autoantigen, myelin basic protein, was also decreased after treatment with ES-DC-TRAIL/MOG. This preventive effect diminished, if the function of CD4⁺CD25⁺ regulatory T cells (Treg) was abrogated by the injection of anti-CD25 mAb into mice before treatment with ES-DC-TRAIL/MOG. The adoptive transfer of CD4⁺CD25⁺ T cells from ES-DC-TRAIL/MOG-treated mice protected the recipient mice from MOG- or myelin basic protein-induced EAE. The number of Foxp3⁺ cells increased in the spinal cords of mice treated with ES-DC-TRAIL/MOG. In vitro experiments showed that TRAIL expressed in genetically modified ES-DC and also in LPS-stimulated splenic macrophages had a capacity to augment the proliferation of CD4⁺CD25⁺ T cells. These results suggest that the prevention of EAE by treatment with ES-DC-TRAIL/MOG is mediated, at least in part, by MOG-reactive CD4⁺CD25⁺ Treg propagated by ES-DC-TRAIL/MOG. For the treatment of organ-specific autoimmune diseases, induction of Treg reactive to the organ-specific autoantigens by the transfer of DC-presenting Ags and simultaneously overexpressing TRAIL therefore appears to be a promising strategy.

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 in part by Grants-in-Aid 12213111, 14370115, 14570421, 14657082, and the Program of Founding Research Centers for Emerging and Reemerging Infectious Disease from the Ministry of Education, Science, Technology, Sports, and Culture, Japan, and a Research Grant for Intractable Diseases from the Ministry of Health, Labour and Welfare, Japan, and grants from the Uehara Memorial Foundation, and by funding from the Meiji Institute of Health Science.

² Y.N. and S.S. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Satoru Senju, Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan. E-mail address: senjusat{at}gpo.kumamoto-u.ac.jp

⁴ Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; ES, embryonic stem cell; PD-L1, programmed death-1 ligand; MBP, myelin basic protein; Treg, regulatory T cell; Trl, T regulatory type 1.

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