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Home List of Titles T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice
Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.3/211866
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- T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice
- Wiede, Florian; Shields, Benjamin J.; Chew, Sock Hui; Kyparissoudis, Konstantinos; van Vliet, Catherine; Galic, Sandra; Tremblay, Michel L.; Russell, Sarah M.; Godfrey, Dale I.; Tiganis, Tony
- 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 type
- Journal article
- Research centre
- Swinburne University of Technology. Faculty of Engineering and Industrial Sciences. Centre for Micro-Photonics
- Journal of Clinical Investigation, Vol. 121, no. 12 (Dec 2011), pp. 4758-4774
- Publication year
- FOR Code(s)
- 11 Medical and Health Sciences
- Autoimmune diseases; Protein tyrosine phosphatases; T cell protein tyrosine phosphatase; T cells; TCPTP
- American Society for Clinical Investigation
- Publisher URL
- Copyright © 2011 The American Society for Clinical Investigation. The published version is reproduced in accordance with the copyright policy of the publisher.
- Additional information
- The authors acknowledge support from the NHMRC of Australia.
- Full text
- Peer reviewed