Thomé Rodolfo, Moore Jason N, Mari Elisabeth R, Rasouli Javad, Hwang Daniel, Yoshimura Satoshi, Ciric Bogoljub, Zhang Guang-Xian, Rostami Abdolmohamad M
Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, Philadelphia, PA, United States.
Department of Neurology, Graduate School of Medical Sciences, Neurological Institute, Kyushu University, Fukuoka, Japan.
Front Immunol. 2017 Oct 27;8:1392. doi: 10.3389/fimmu.2017.01392. eCollection 2017.
Peripheral tolerance to autoantigens is induced suppression of self-reactive lymphocytes, stimulation of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Interleukin (IL)-27 induces tolerogenic DCs and Treg cells; however, it is not known whether IL-27 is important for tolerance induction. We immunized wild-type (WT) and IL-27 receptor (WSX-1) knockout mice with MOG for induction of experimental autoimmune encephalomyelitis and intravenously (i.v.) injected them with MOG after onset of disease to induce i.v. tolerance. i.v. administration of MOG reduced disease severity in WT mice, but was ineffective in mice. IL-27 signaling in DCs was important for tolerance induction, whereas its signaling in T cells was not. Further mechanistic studies showed that IL-27-dependent tolerance relied on cooperation of distinct subsets of spleen DCs with the ability to induce T cell-derived IL-10 and IFN-γ. Overall, our data show that IL-27 is a key cytokine in antigen-induced peripheral tolerance and may provide basis for improvement of antigen-specific tolerance approaches in multiple sclerosis and other autoimmune diseases.
自身抗原的外周耐受是通过抑制自身反应性淋巴细胞、刺激耐受性树突状细胞（DC）和调节性T（Treg）细胞来诱导的。白细胞介素（IL）-27可诱导耐受性DC和Treg细胞；然而，尚不清楚IL-27对耐受诱导是否重要。我们用髓鞘少突胶质细胞糖蛋白（MOG）免疫野生型（WT）和IL-27受体（WSX-1）基因敲除小鼠以诱导实验性自身免疫性脑脊髓炎，并在疾病发作后静脉内（i.v.）给它们注射MOG以诱导静脉内耐受。静脉内给予MOG可降低WT小鼠的疾病严重程度，但对基因敲除小鼠无效。DC中的IL-27信号传导对耐受诱导很重要，而其在T细胞中的信号传导则不然。进一步的机制研究表明，IL-27依赖性耐受依赖于具有诱导T细胞衍生的IL-10和干扰素-γ能力的不同脾DC亚群的合作。总体而言，我们的数据表明IL-27是抗原诱导的外周耐受中的关键细胞因子，并可能为改善多发性硬化症和其他自身免疫性疾病中的抗原特异性耐受方法提供依据。
