Swinburne
Browse

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

Download (4.76 MB)
journal contribution
posted on 2024-08-06, 09:30 authored by Florian Wiede, Benjamin J. Shields, Sock Hui Chew, Konstantinos Kyparissoudis, Catherine van Vliet, Sandra Galic, Michel L. Tremblay, Sarah RussellSarah Russell, Dale I. Godfrey, Tony Tiganis
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.

Funding

National Health and Medical Research Council

Australian Research Council

History

Available versions

PDF (Published version)

ISSN

0021-9738

Journal title

Journal of Clinical Investigation

Volume

121

Issue

12

Pagination

16 pp

Publisher

American Society for Clinical Investigation

Copyright statement

Copyright © 2011 The American Society for Clinical Investigation. The published version is reproduced in accordance with the copyright policy of the publisher.

Language

eng

Usage metrics

    Publications

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC