Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity

J Immunol. 2012 Jun 1;188(11):5397-407. doi: 10.4049/jimmunol.1103210. Epub 2012 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / biosynthesis
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • CD11c Antigen / biosynthesis
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Dendritic Cells / enzymology*
  • Dendritic Cells / immunology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / deficiency*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / physiology
  • Splenomegaly / genetics
  • Splenomegaly / immunology
  • Splenomegaly / pathology
  • Th1 Cells / cytology
  • Th1 Cells / immunology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Autoantibodies
  • CD11c Antigen
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse