Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
PLoS One. 2013;8(1):e54884. doi: 10.1371/journal.pone.0054884. Epub 2013 Jan 21.
Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
Fms 样酪氨酸激酶 3 配体（Flt3L）是树突状细胞（DC）的主要分化和存活因子。此外，Flt3L 参与 DC 和调节性 T 细胞（Treg）之间的稳态反馈环。我们之前已经表明，Flt3L 在类风湿关节炎（RA）的滑液中积累，并且局部暴露于 Flt3L 会加重小鼠的关节炎，这表明它可能参与 RA 的发病机制。在本研究中，我们研究了 Flt3L 在实验性抗原诱导的关节炎中的 DC 群体、Treg 以及炎症反应中的作用。通过 mBSA 免疫小鼠膝关节内局部注射 mBSA 诱导关节炎，并通过每日腹腔内注射提供 Flt3L。对脾脏和淋巴结的流式细胞术分析显示，用 Flt3L 处理的小鼠中 DC 及其随后的 Treg 形成增加。Flt3L 治疗还与 mBSA 特异性抗体产生减少和促炎细胞因子 IL-6 和 TNF-α水平降低相关。对 mBSA 注射关节的形态学评估显示，Flt3L 治疗小鼠的关节破坏减少。在过继转移实验中进一步挑战了 DC 在 mBSA 关节炎中的作用。从 mBSA 免疫的小鼠中转移 DC 与 T 细胞一起，使幼稚受体易患关节炎和产生 mBSA 特异性抗体。我们提供了实验证据表明，Flt3L 具有强大的免疫调节特性。Flt3L 促进 Treg 细胞的形成，并通过这种机制减轻小鼠抗原诱导关节炎的严重程度。我们认为，全身性高水平的 Flt3L 有可能调节自身反应性和自身免疫。
