Protein tyrosine phosphatase PTPN22 regulates IL-1β dependent Th17 responses by modulating dectin-1 signaling in mice

Harriet A. Purvis*, Fiona Clarke, Christine K. Jordan, Cristina Sanchez Blanco, Georgina H. Cornish, Xuezhi Dai, David J. Rawlings, Rose Zamoyska, Andrew P. Cope

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
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Abstract

A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal β-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and Ptpn22−/− mutant mice, were pulsed with OVA323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated Ptpn22−/− BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1β dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated Ptpn22−/− BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing Ptpn22R619W (the mouse orthologue of human PTPN22R620W) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease.

Original languageEnglish
Pages (from-to)306-315
Number of pages10
JournalEuropean Journal of Immunology
Volume48
Issue number2
Early online date20 Oct 2017
DOIs
Publication statusPublished - 28 Feb 2018

Keywords

  • Autoimmunity
  • Dectin-1
  • IL-17
  • IL-1β
  • PTPN22

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