調節性T細胞在動脈粥狀硬化進程及逆轉過程中的作用

Abstract

寄生蟲感染在開發中國家是個常見疾病。最近的研究指出，原住民罹患心血管疾病的風險較低，這可能與他們腸道微生物群與腸道寄生蟲感染的協同演化有關。先前的研究表明寄生蟲感染，如多型性螺旋線蟲（Heligmosomoides polygyrus）和 鼠鞭蟲（Trichuris muris）能誘導腸道中的第二型免疫反應和調節性T細胞（Tregs）擴增。然而，腸道寄生蟲感染與心血管疾病之間的關係尚不明確。因此我們假設寄生蟲感染所引起的第二型免疫反應以及調控型T細胞能夠介導動脈粥狀硬化斑塊的復原。我們觀察到，相比於對照組，全身性的FoxP3+ CD4 T細胞及GATA3+ 輔助型T細胞在受寄生蟲感染的小鼠血液中顯著增加。對寄生蟲感染的動脈粥狀硬化小鼠進行主動脈根部切片進行了連續定量分析證實了斑塊的逆轉，而免疫組織化學染色進一步觀察到巨噬細胞含量的顯著下降。此外，在斑塊逆轉期間，我們也觀察到主動脈弓中CD4 T細胞數量的明顯增加，以及CD11b+ F4/80+ 巨噬細胞的減少。這表示在寄生蟲感染的動脈粥樣硬化小鼠中，調節性 T 細胞可能在斑塊逆轉期間浸潤至動脈粥樣硬化斑塊中。總之，我們透過誘導全身性的調控型T細胞和第二型免疫反應，提供了一種可行且新穎的治療技術，用以治療動脈粥狀硬化。

Helminth infection is a common disease in developing countries. Recent studies indicate that indigenous people are less likely to suffer from cardiovascular diseases, which may be correlated to their intestinal Microbiome changes coevolved with intestinal helminth infection. Previous studies showed that helminth infection, Heligmosomoides polygyrus (H. polygyrus) and Trichuris muris (T. muris), can induce type 2 immune responses and regulatory T cells (Tregs) expansion in the gut. However, the links between intestinal helminth infection and cardiovascular diseases are poorly understood. We hypothesized that Tregs or type 2 immunity induction by H. polygyrus or T. muris infection mediates atherosclerotic plaque regression. We observed systemic FOXP3+ CD4 Treg and GATA3+ T helper 2 (Th2) cells are significantly increased in the blood of H. polygyrus and T. muris infected mice than in control mice. Serial quantitative analysis of aortic root sections from H. polygyrus or T. muris infected atherosclerotic mice confirmed plaque regression, and a significant decrease of macrophage contents was observed by immunohistochemistry. Furthermore, we also observed a significant increase in the number of CD4 T cells and a decrease in CD11b+ F4/80+ macrophages in the aortic arch during plaque regression. It indicated regulatory T cells might infiltrate into atherosclerotic plaques during plaque regression in H. polygyrus or T. muris-infected atherosclerotic mice. Overall, we may provide a novel therapeutic for the resolution of atherosclerosis by helminth-induced systemic Treg and Type 2 immunity inductions.