Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US.
J Neuroinflammation. 2024 May 31;21(1):144. doi: 10.1186/s12974-024-03126-3.
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.
累积证据表明，干扰素（IFN）-γ 在多发性硬化症和动物模型实验性自身免疫性脑脊髓炎（EAE）中具有致病和保护作用。然而，IFN-γ 发挥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 模型具有治疗作用。用 IFN-γ 治疗慢性 EAE 小鼠的脊髓中调节性 T（Treg）细胞的频率显著增加，而对 Th1 和 Th17 细胞没有影响。一致地，耗尽表达 FOXP3 的细胞阻断了 IFN-γ 的保护作用，表明 IFN-γ 的治疗效果依赖于 Treg 细胞的存在。然而，IFN-γ 并没有在体外直接诱导 Treg 细胞的分化。体内给予阻断白细胞介素（IL）-10、转化生长因子（TGF）-β 或程序性死亡（PD）-1 的抗体，表明 IFN-γ 在 EAE 中的保护作用也依赖于 TGF-β 和 PD-1，但不依赖于 IL-10，表明 IFN-γ 可能通过抗原呈递细胞对 Treg 细胞发挥间接作用。事实上，IFN-γ 治疗以依赖信号转导和转录激活因子（STAT）-1 的方式增加了脾脏 CD11b 髓样细胞中表达 TGF-β-潜伏相关肽（LAP）和程序性死亡配体 1（PD-L1）的亚群的频率。此外，用 IFN-γ 和髓鞘少突胶质细胞糖蛋白（MOG）肽预处理的 EAE 小鼠的脾 CD11b 细胞表现出耐受表型，具有通过分泌 TGF-β 诱导幼稚 CD4 T 细胞转化的能力。值得注意的是，将来自 IFN-γ 治疗的 EAE 小鼠的脾 CD11b 细胞过继转移到未治疗的受体小鼠中，可改善 EAE 的临床症状，并限制单核细胞和效应辅助性 T 细胞在中枢神经系统中的浸润。这些结果揭示了一种新的细胞和分子机制，即 IFN-γ 通过赋予脾脏 CD11b 髓样细胞具有耐受性和治疗活性，从而在 EAE 中发挥有益作用。
