Expression of the tyrosine phosphatase SRC homology 2 domain-containing protein tyrosine phosphatase 1 determines T cell activation threshold and severity of experimental autoimmune encephalomyelitis

J Immunol. 2002 May 1;168(9):4511-8. doi: 10.4049/jimmunol.168.9.4511.

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a CD4 Th1-mediated inflammatory demyelinating disorder of the CNS and a well-established animal model for multiple sclerosis. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAE pathogenesis, we immunized B10.PL mice heterozygous for deletion of the SHP-1 gene (me(v+/-)) and B10.PL wild-type mice with the immunodominant epitope of myelin basic protein (MBP Ac1-11). T cell proliferation and IFN-gamma production were significantly increased in me(v+/-) mice after immunization with MBP Ac1-11. The frequency of MBP Ac1-11-specific CD4 T cells, analyzed by staining with fluorescently labeled tetramers (MBP1-11[4Y]: I-A(u) complexes), was increased in the draining lymph node cells of me(v+/-) mice compared with wild-type mice. In addition, me(v+/-) mice developed a more severe course of EAE with epitope spreading to proteolipid protein peptide 43-64. Finally, expansion of MBP Ac1-11-specific T cells in response to Ag was enhanced in me(v+/-) T cells, particularly at lower Ag concentrations. These data demonstrate that the level of SHP-1 plays an important role in regulating the activation threshold of autoreactive T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Immunoglobulin Variable Region / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Activation*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myelin Basic Protein / immunology
  • Myelin Proteolipid Protein / immunology
  • Peptide Fragments / immunology
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*

Substances

  • Cytokines
  • Immunoglobulin Variable Region
  • Intracellular Signaling Peptides and Proteins
  • Myelin Basic Protein
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • myelin basic protein 1-11
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse