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

Abstract

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.

• Authors: Florian Wiede, Benjamin J Shields, Sock Hui Chew, Konstantinos Kyparissoudis, Catherine van Vliet, Sandra Galic, Michel L Tremblay, Sarah M Russell, Dale I Godfrey, Tony Tiganis
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 12 Pg. 4758-74 (Dec 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 22080863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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