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 mice.
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-gamma, 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.
Tomizawa
Takeshi
T
Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
Kaneko
Yuka
Y
Kaneko
Yoriaki
Y
Saito
Yasuyuki
Y
Ohnishi
Hiroshi
H
Okajo
Jun
J
Okuzawa
Chie
C
Ishikawa-Sekigami
Tomomi
T
Murata
Yoji
Y
Okazawa
Hideki
H
Okamoto
Koichi
K
Nojima
Yoshihisa
Y
Matozaki
Takashi
T
D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008817:Mice, Mutant Strains; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C445081:myelin oligodendrocyte glycoprotein (35-55)