Institute of Virology, University of Zürich, Zürich, Switzerland.
Gene Ther. 2015 May;22(5):382-90. doi: 10.1038/gt.2015.6. Epub 2015 Mar 5.
We have recently shown that targeted expression of myelin oligodendrocyte glycoprotein (MOG) to dendritic cells with self-inactivating-lentivirus vectors induces antigen-specific tolerance in naive antigen-specific CD4+ T cells and protects mice from experimental autoimmune encephalomyelitis (EAE). In the present study, we demonstrate that this approach also induces tolerance of activated antigen-specific CD4+ T cells and completely protects mice from passive EAE induction. Tolerance induction did not correlate with the depletion of the preactivated antigen-specific CD4+ T cells. However, upon isolation and in vitro re-stimulation at day 6 after adoptive transfer the MOG-specific CD4+ T cells from the non-tolerized mice produced large amounts of inflammatory cytokines, whereas those from tolerized mice did not. This unresponsiveness correlated with the upregulation of regulatory molecules associated with anergy and regulatory T cells (Tregs). The in vivo depletion of Tregs resulted in EAE susceptibility of the tolerized animals, suggesting that these cells have indeed a role in tolerance induction/maintenance.
我们最近的研究表明，利用自我失活慢病毒载体靶向表达髓鞘少突胶质细胞糖蛋白（MOG）至树突状细胞，可诱导幼稚抗原特异性 CD4+T 细胞产生抗原特异性耐受，并保护小鼠免受实验性自身免疫性脑脊髓炎（EAE）的影响。在本研究中，我们证明了该方法也可诱导活化的抗原特异性 CD4+T 细胞耐受，并完全保护小鼠免受被动 EAE 的诱导。耐受诱导与预先激活的抗原特异性 CD4+T 细胞的耗竭无关。然而，在过继转移后第 6 天分离和体外再刺激时，非耐受小鼠来源的 MOG 特异性 CD4+T 细胞产生大量的炎症细胞因子，而耐受小鼠来源的细胞则没有。这种无反应性与与失能和调节性 T 细胞（Tregs）相关的调节分子的上调相关。体内耗尽 Tregs 会导致耐受动物出现 EAE 易感性，这表明这些细胞在诱导和维持耐受中确实发挥作用。
