Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI)-Paris, F-75013 Paris, France.
Centre de Recherche en Cancérologie de Lyon, Labex DEVweCAN, INSERM, CNRS, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2014043118.
CD4Foxp3 regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.
CD4Foxp3 调节性 T（Treg）细胞是自身免疫性疾病的中枢调节剂。然而，Treg 细胞介导的针对组织特异性自身免疫的抑制作用的时间和位置仍未确定。在这里，我们通过研究肿瘤坏死因子（TNF）受体 2（TNFR2）信号在实验性自身免疫性脑脊髓炎（EAE）中的 Treg 细胞中的作用来解决这些问题，EAE 是多发性硬化症的模型。我们发现，在中枢神经系统疾病高峰期，表达 TNFR2 的 Treg 细胞对于抑制 EAE 至关重要，但在疾病发作时对淋巴组织中的 T 细胞启动没有影响。从机制上讲，TNFR2 信号维持了具有持续表达 CTLA-4 和 Blimp-1 的功能性 Treg 细胞，允许在发炎的中枢神经系统中主动抑制致病性 T 细胞。通过用 TNF 和 TNFR2 激动剂和拮抗剂治疗小鼠，进一步证实了 Treg 细胞的这种晚期作用。我们的研究结果表明，内源性 Treg 细胞通过在明显炎症时在靶组织中发挥作用特异性地抑制自身免疫性疾病。此外，它们为 TNF 拮抗剂治疗患者的一些不良反应提供了一种机制上的见解。
