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Protein tyrosine phosphatase PTPN22 regulates IL-1β dependent Th17 responses by modulating dectin-1 signaling in mice.
- Source :
-
European journal of immunology [Eur J Immunol] 2018 Feb; Vol. 48 (2), pp. 306-315. Date of Electronic Publication: 2017 Oct 20. - Publication Year :
- 2018
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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 <superscript>-/-</superscript> mutant mice, were pulsed with OVA <subscript>323-339</subscript> 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 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing Ptpn22 <superscript>R619W</superscript> (the mouse orthologue of human PTPN22 <superscript>R620W</superscript> ) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22 <superscript>R619W</superscript> 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.<br /> (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Cells, Cultured
Coculture Techniques
Humans
Interleukin-1beta metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Polymorphism, Single Nucleotide
Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics
Risk
Signal Transduction
Autoimmune Diseases genetics
Dendritic Cells physiology
Lectins, C-Type metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 22 metabolism
Th17 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 48
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 28948613
- Full Text :
- https://doi.org/10.1002/eji.201747092