PDF(Pubmed)
Abstract：
Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-γ was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-γ, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. However, IFN-γ did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-β or program death (PD)-1, revealed that the protective effects of IFN-γ in EAE were also dependent on TGF-β and PD-1, but not on IL-10, suggesting that IFN-γ might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-γ treatment increased the frequency of a subset of splenic CD11b+ myeloid cells expressing TGF-β-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b+ cells from EAE mice preconditioned in vitro with IFN-γ and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4+ T cells mediated by secretion of TGF-β. Remarkably, adoptive transfer of splenic CD11b+ cells from IFN-γ-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism whereby IFN-γ promotes beneficial effects in EAE by endowing splenic CD11b+ myeloid cells with tolerogenic and therapeutic activities.
摘要：
累积证据表明,干扰素(IFN)-γ在多发性硬化和动物模型中具有致病和保护作用,实验性自身免疫性脑脊髓炎(EAE)。然而,IFN-γ有益作用的潜在机制尚不清楚。在这项研究中,我们发现IFN-γ对慢性，复发缓解，和慢性进行性EAE模型。用IFN-γ处理的慢性EAE小鼠脊髓中调节性T（Treg）细胞的频率显着增加，对Th1和Th17细胞没有影响。始终如一，表达FOXP3的细胞的消耗阻断了IFN-γ的保护作用，表明IFN-γ的治疗效果取决于Treg细胞的存在。然而,IFN-γ不触发Treg细胞的直接体外分化。体内施用针对白介素（IL）-10，转化生长因子（TGF）-β或程序性死亡（PD）-1的阻断抗体，表明IFN-γ在EAE中的保护作用也取决于TGF-β和PD-1，但不取决于IL-10，这表明IFN-γ可能对通过抗原呈递细胞起作用的Treg细胞具有间接作用。的确,IFN-γ治疗增加了以信号转导和转录激活因子(STAT)-1依赖性方式表达TGF-β-潜伏相关肽(LAP)和程序性死亡配体1(PD-L1)的脾CD11b+骨髓细胞亚群的频率。此外，用IFN-γ和髓鞘少突胶质细胞糖蛋白（MOG）肽体外预处理的EAE小鼠的脾CD11b细胞表现出耐受原性表型，能够诱导由TGF-β分泌介导的幼稚CD4T细胞的转化。值得注意的是,将IFN-γ处理的EAE小鼠的脾CD11b细胞过继转移到未处理的受体小鼠中，改善了EAE的临床症状，并限制了中枢神经系统中单核细胞和效应辅助T细胞的浸润。这些结果揭示了一种新的细胞和分子机制，其中IFN-γ通过赋予脾CD11b骨髓细胞耐受原和治疗活性来促进EAE中的有益作用。
