调控固有淋巴细胞分化—调节性T细胞抑制动脉粥样硬化新机制

We and others previously reported that regulatory T cells (Treg) play an important role in maintaining vascular homeostasis after damage and protecting against atherosclerosis(AS) by regulating innate and adaptive immune–mediated responses. Innate lymphoid cell (ILC) is a newly discovered subset of innate immune cell， differential cytokine production endows different ILC subsets with specific functions in both protective immunity against pathogens and immune/inflammatory diseases like AS. Our preliminary data reveals adoptive transfer of Tregs decreases number of IFN-γ+ ILC1 in ApoE-/- mice and attenuates AS. On the basis of our findings, We hypothesize that a novel function of Treg in AS is related to its ability to modulate differentiation of ILCs during atherogenesis. We will test our hypotheses in the following specific aims. Specific Aim 1 will seek to understand whether Treg is associated with ILCs homeostasis in ApoE-/- mice. Specific Aim 2 will examine the effect of in vivo cell depletion、expansion and adoptive transfer of Treg on ILCs differentition and atherosclerotic plaque formation. Specific Aim 3 will dissect signaling pathways that orchestrate Treg dependent differentiation of ILCs. This study is expected to provide novel insights into the immune regulatory mechanisms of atherogenic responses, and may lead to new therapeutic approaches in prevention and treatment of atherosclerosis.

包括我们在内的大量研究表明，调节性T细胞（Treg）通过调控天然免疫和获得性免疫维持血管稳态，抑制动脉粥样硬化(AS)。固有淋巴细胞（ILCs）是一类新发现的天然免疫细胞，不同ILC亚群通过分泌细胞因子参与了包括AS在内的许多免疫炎症相关疾病的发生发展。Treg是否调控ILCs分化进而抑制AS发生尚不清楚。我们的预实验研究发现，向ApoE-/-小鼠转输Treg，脾脏ILC1比例明显减少，同时动脉斑块面积减少，提示Treg可能通过调控ILCs分化抑制AS。本项目拟进一步明确其作用和机制。项目将通过观察AS时Treg和ILCs各亚群的变化规律；探讨在体清除、扩增和过继转移Treg对ILCs分化和AS的影响；以及研究Treg调控ILCs分化的作用和分子机制，来揭示Treg 介导的这种全新的免疫调节机制在AS形成中的作用。结果将有助于完善AS发病机制，并为Treg 的转化医学研究提供依据。

通过体外实验和在体实验，本项目：.1.首次发现报道ILC1促进动脉粥样硬化发生发展并阐明其分子机制；.2.首次发现报道调节性T细胞（Treg）通过调节ILC2分化，抑制动脉粥样硬化，并阐明其分子机制；.3.首次发现报道Sestrin2蛋白通过Treg调控心肌缺血后心室重构；.4.发现Treg对ILC前体细胞分化的调控作用和分子机制；.5.发现ILCreg在心肌缺血中的作用。.结果有助于阐明动脉粥样硬化和心肌重构炎症反应的机制，为动脉粥样硬化及其并发症的防治提供理论依据。