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

Shatakshi Sood, Rebecca J Brownlie, Celine Garcia, Graeme Cowan, Robert J Salmond, Shimon Sakaguchi, Rose Zamoyska

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The cytoplasmic phosphatase, PTPN22 (protein tyrosine phosphatase non-receptor type is a negative regulator of T cell signalling. 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 ZAP-70, which upon exposure to fungal antigens 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 to 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 T helper cell differentiation away from the Th17 lineage, which is pathogenic in this setting, to a more Th1/Treg 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 autoimmue diseases.
Original languageEnglish
Pages (from-to)429-440
Number of pages12
JournalThe Journal of Immunology
Issue number2
Early online date5 Jul 2016
Publication statusPublished - 15 Jul 2016


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