Chen Szu-Ying, Hsu Wan-Tseng, Chen Yi-Lien, Chien Chien-Hui, Chiang Bor-Luen
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Autoimmun. 2016 Apr;68:75-85. doi: 10.1016/j.jaut.2016.02.002. Epub 2016 Feb 19.
Rheumatoid arthritis (RA) is an autoimmune disease in which dysregulated immune cells primarily target synovial joints. Despite recent advances in the treatment of RA, including the introduction of biologic therapies and employment of combination disease-modifying antirheumatic drug strategies, remission rates remain suboptimal. Previous studies have demonstrated that the adoptive transfer of induced regulatory T cells (iTregs) was effective in treating a murine model of collagen-induced arthritis (CIA). The objective of this study was to develop optimal potential iTreg-based therapy for CIA by adoptively transferring LAG3(+) Treg-of-B cells. B-cell-induced Treg-of-B cells expressed LAG3 but not Foxp3 (designated LAG3(+) Treg-of-B), and secreted IL-4, IL-10, and TGF-β. Furthermore, LAG3(+) Treg-of-B cells suppressed the proliferation of CD4(+)CD25(-) responder T cells through both LAG3 and IL-10 production. In the murine CIA model, adoptive transfer of LAG3(+) Treg-of-B cells alleviated the joint severity as well as local and systemic inflammation. Treatment with LAG3(+) Treg-of-B cells also promoted IL-10 production in lymphocytes isolated from the spleen and draining lymph nodes. Moreover, mice receiving LAG3(+) Treg-of-B cell treatment showed significantly less pronounced osteolysis in the hind footpads, which correlated with the downregulation of tartrate-resistant acid phosphatase expression. In conclusion, we identified a novel subset of Tregs for CIA treatment. This insight may facilitate exploring novel regulatory T-cell-based therapies for human autoimmune diseases.
类风湿性关节炎（RA）是一种自身免疫性疾病，其中失调的免疫细胞主要靶向滑膜关节。尽管近年来RA的治疗取得了进展，包括引入生物疗法和采用联合改善病情抗风湿药物策略，但缓解率仍不尽人意。先前的研究表明，过继转移诱导调节性T细胞（iTregs）在治疗胶原诱导性关节炎（CIA）的小鼠模型中是有效的。本研究的目的是通过过继转移LAG3(+) B细胞来源的调节性T细胞来开发针对CIA的最佳潜在iTreg疗法。B细胞诱导的B细胞来源的调节性T细胞表达LAG3但不表达Foxp3（命名为LAG3(+) B细胞来源的调节性T细胞），并分泌IL-4、IL-10和TGF-β。此外，LAG3(+) B细胞来源的调节性T细胞通过产生LAG3和IL-10抑制CD4(+)CD25(-)反应性T细胞的增殖。在小鼠CIA模型中，过继转移LAG3(+) B细胞来源的调节性T细胞减轻了关节严重程度以及局部和全身炎症。用LAG3(+) B细胞来源的调节性T细胞治疗还促进了从脾脏和引流淋巴结分离的淋巴细胞中IL-10的产生。此外，接受LAG3(+) B细胞来源的调节性T细胞治疗的小鼠后足垫的骨溶解明显减轻，这与抗酒石酸酸性磷酸酶表达的下调相关。总之，我们鉴定出了一种用于治疗CIA的新型调节性T细胞亚群。这一发现可能有助于探索基于调节性T细胞的新型人类自身免疫性疾病治疗方法。
