Protein tyrosine phosphatase PTPN22 regulates IL‐1β dependent Th17 responses by modulating dectin‐1 signaling in mice |
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| Authors: | Harriet A Purvis Fiona Clarke Christine K Jordan Cristina Sanchez Blanco Georgina H Cornish Xuezhi Dai David J Rawlings Rose Zamoyska Andrew P Cope |
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| Affiliation: | 1. Academic Department of Rheumatology, Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, UK;2. Seattle Children's Research Institute and Departments of Pediatrics and Immunology, University of Washington School of Medicine, Seattle, Washington, USA;3. Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK |
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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. |
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| Keywords: | Autoimmunity Dectin‐1 IL‐1β IL‐17 PTPN22 |
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