4.5 Article

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

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

资金

  1. Arthritis Research UK [20218, 20525]
  2. Wellcome Trust Investigator Award [096669AIA]
  3. NIH [DP3-DK097672, DP3-DK111802]
  4. Children's Guild Association Endowed Chair in Pediatric Immunology
  5. Benaroya Family Gift Fund
  6. 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]
  7. 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]
  8. Versus Arthritis [20525, 20218] Funding Source: researchfish

向作者/读者索取更多资源

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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