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Resistance to Experimental Autoimmune Encephalomyelitis and Impaired T Cell Priming by Dendritic Cells in Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Mutant Mice¹

Takeshi Tomizawa^2,*, Yuka Kaneko^2,,, Yoriaki Kaneko^3,*, Yasuyuki Saito^*, Hiroshi Ohnishi, Jun Okajo^*, Chie Okuzawa^*, Tomomi Ishikawa-Sekigami^*, Yoji Murata, Hideki Okazawa, Koichi Okamoto, Yoshihisa Nojima^* and Takashi Matozaki^3,

^* Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan; Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan; and Department of Neurology, Gunma University Graduate School of Medicine, Gunma, Japan

Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of CD11c⁺ dendritic cells (DCs) and macrophages. In this study, we show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein (MOG (35–55)). The MOG (35–55)-induced proliferation of, and production of IFN-, IL-2, and IL-17, by T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. The abilities of splenic DCs from mutant mice to stimulate an allogenic MLR and to prime Ag-specific T cells were reduced. Both IL-12-stimulated and TLR-dependent cytokine production by DCs of mutant mice were also impaired. Finally, SHPS-1 mutant mice were resistant to induction of EAE by adoptive transfer of MOG (35–55)-specific T cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the CNS and other autoimmune diseases.

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 Scientific Research on Priority Areas Cancer, a Grant-in-Aid for Scientific Research (B) and (C), a grant of Initiatives for Attractive Education in Graduate Schools, and a grant of the 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

² T.T., and Yu.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Takashi Matozaki, Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan; E-mail address: matozaki{at}showa.gunma-u.ac.jp or Dr. Yoriaki Kaneko, Department of Clinical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8512, Japan; E-mail address: ykaneko{at}showa.gunma-u.ac.jp

⁴ Abbreviations used in this paper: DC, dendritic cell; BMDC, DC derived from bone marrow; EAE, experimental autoimmune encephalomyelitis; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; ODN, oligodeoxynucleotide; SHP, Src homology 2 domain-containing protein tyrosine phosphatase; SHPS-1, SHP substrate-1; WT, wild type.

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