Academic Department of Rheumatology, Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
Seattle Children's Research Institute and Departments of Pediatrics and Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
Eur J Immunol. 2018 Feb;48(2):306-315. doi: 10.1002/eji.201747092. Epub 2017 Oct 20.
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 OVA 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 Ptpn22 (the mouse orthologue of human PTPN22 ) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22 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.
PTPN22 基因中的单核苷酸多态性是导致多种自身免疫性疾病发生的强烈遗传风险因素。PTPN22 调节免疫受体下游的 Syk 和 Src 家族激酶。真菌β-葡聚糖受体 dectin-1 通过 Syk 发出信号，dectin-1 的刺激可诱导小鼠模型发生关节炎。我们研究了 PTPN22 是否调节 dectin-1 依赖性免疫反应。从 C57BL/6 野生型（WT）和 Ptpn22 突变型小鼠生成的骨髓来源树突状细胞（BMDC）用 OVA 和 dectin-1 激动剂几丁质处理，并在体外与 OT-II T 细胞共培养或过继转移到 OT-II 小鼠中，通过免疫测定法确定 T 细胞反应。与 WT 相比，dectin-1 激活的 Ptpn22 BMDC 在体外和体内以 IL-1β 依赖性方式增强 T 细胞分泌 IL-17。免疫印迹显示，与 WT 相比，dectin-1 激活的 Ptpn22 BMDC 显示出增强的 Syk 和 Erk 磷酸化。表达 Ptpn22（人类 PTPN22 的小鼠同源物）的 BMDC 的 dectin-1 激活也导致 IL-1β 分泌和 T 细胞依赖性 IL-17 反应增加，表明在 dectin-1 的背景下，PTPN22 作为一种功能丧失变异起作用。这些发现强调了 PTPN22 是 dectin-1 信号的新型调节剂，为先天受体信号转导中遗传赋予的扰动与自身免疫性疾病风险之间提供了联系。
