Sood, S., Brownlie, R. J., Garcia, C., Cowan, G., Salmond, R. J., Sakaguchi, S. and Zamoyska, R. (2016) Loss of the protein tyrosine phosphatase PTPN22 reduces mannan-induced autoimmune arthritis in SKG mice. Journal of Immunology, 197(2), pp. 429-440. (doi: 10.4049/jimmunol.1502656) (PMID:27288531) (PMCID:PMC4932175)
|
Text
122557.pdf - Published Version Available under License Creative Commons Attribution. 1MB |
Abstract
The cytoplasmic phosphatase, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), is a negative regulator of T cell signaling. Genome-wide association studies have shown that single-nucleotide polymorphisms in PTPN22 confer an increased risk of developing multiple autoimmune diseases in humans. The precise function of PTPN22 and how the variant protein contributes to autoimmunity is not well understood. To address this issue, we investigated the effect of PTPN22 deficiency on disease susceptibility in a mouse model of autoimmune arthritis. The SKG mouse expresses a hypomorphic mutant allele of ZAP70, which, upon exposure to fungal Ags, predisposes the mice to a CD4+ T cell–mediated autoimmune arthritis that closely resembles rheumatoid arthritis in humans. Surprisingly, SKG Ptpn22−/− mice developed less severe mannan-induced arthritis compared with SKG mice. Diminution of disease was not due to significant alterations in thymocyte development or repertoire selection in SKG Ptpn22−/− mice, even though T cell–mediated signal transduction was improved. Instead, Ptpn22 deficiency appeared to bias CD4 Th cell differentiation away from the Th17 lineage, which is pathogenic in this setting, to a more Th1/T regulatory–focused response. These data show that even small perturbations in TCR signal transduction pathways can have profound consequences on the differentiation of T cell lineages and thus for the development of autoimmune diseases.
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Sood, Dr Shatakshi |
Authors: | Sood, S., Brownlie, R. J., Garcia, C., Cowan, G., Salmond, R. J., Sakaguchi, S., and Zamoyska, R. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Journal of Immunology |
Publisher: | American Association of Immunologists |
ISSN: | 0022-1767 |
ISSN (Online): | 1550-6606 |
Published Online: | 10 June 2016 |
Copyright Holders: | Copyright © 2016 The Authors |
First Published: | First published in Journal of Immunology 197(2): 429-440 |
Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record