Loss of the protein tyrosine phosphatase PTPN22 reduces mannan-induced autoimmune arthritis in SKG mice

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)

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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 > Institute of Infection Immunity and Inflammation
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

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