期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 48, 期 2, 页码 306-315出版社
WILEY
DOI: 10.1002/eji.201747092
关键词
Autoimmunity; Dectin-1; IL-1 beta; IL-17; PTPN22
类别
资金
- Arthritis Research UK [20218, 20525]
- Wellcome Trust Investigator Award [096669AIA]
- NIH [DP3-DK097672, DP3-DK111802]
- Children's Guild Association Endowed Chair in Pediatric Immunology
- Benaroya Family Gift Fund
- National Institute for Health Research (NIHR) BioResource Clinical Research facility based at Guy's and St. Thomas' NHS Foundation Trust and King's College London [guysbrc-2012-17]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London [guysbrc-2012-17]
- Versus Arthritis [20525, 20218] Funding Source: researchfish
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 beta-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 OVA(323-339) 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-1 beta 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 Ptpn22(R619W) (the mouse orthologue of human PTPN22(R620W)) also resulted in increased IL-1 beta secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22(R619W) 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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