title: Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity.
abstract: Dendritic cells (DCs) promote immune responses to foreign Ags and immune tolerance to self-Ags. Deregulation of DCs is implicated in autoimmunity, but the molecules that regulate DCs to protect against autoimmunity have remained unknown. In this study, we show that mice lacking the protein tyrosine phosphatase Shp1 specifically in DCs develop splenomegaly associated with more CD11c(+) DCs. Splenic DCs from the mutant mice showed upregulation of CD86 and CCR7 expression and of LPS-induced production of proinflammatory cytokines. The mice manifested more splenic Th1 cells, consistent with the increased ability of their DCs to induce production of IFN-γ by Ag-specific T cells in vitro. The number of splenic CD5(+)CD19(+) B-1a cells and the serum concentrations of Igs M and G2a were also increased in the mutant mice. Moreover, aged mutant mice developed glomerulonephritis and interstitial pneumonitis together with increased serum concentrations of autoantibodies. Shp1 is thus a key regulator of DC functions that protects against autoimmunity.
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kaneko
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Takenori
authors.initials: T
authors.lastname: Kotani
authors.forename: Hideki
authors.initials: H
authors.lastname: Okazawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwamura
authors.forename: Miho
authors.initials: M
authors.lastname: Sato-Hashimoto
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Keiju
authors.initials: K
authors.lastname: Hiromura
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusakari
authors.forename: Yoriaki
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D039521:CD11c Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D039521:CD11c Antigen; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse