T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

J Clin Invest. 2011 Dec;121(12):4758-74. doi: 10.1172/JCI59492. Epub 2011 Nov 14.


Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8(+) T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8(+) T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / etiology*
  • Autoimmune Diseases / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Immune Tolerance / immunology*
  • Inflammation / blood
  • Inflammation / genetics
  • Inflammation / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / physiology*
  • Radiation Chimera
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / enzymology*
  • T-Lymphocyte Subsets / immunology
  • Thymocytes / pathology
  • ZAP-70 Protein-Tyrosine Kinase / physiology
  • src-Family Kinases / metabolism


  • Antibodies, Antinuclear
  • Receptors, Antigen, T-Cell
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse