T cell plasticity in atherosclerosis

描述（由申请人提供）：辅助性T细胞1（Th 1）发挥促动脉粥样硬化作用，而调节性T细胞（Treg）表现出抗炎作用。Th 17（CD 4 +IL-17+）细胞在动脉粥样硬化中的作用仍存在争议。有证据表明存在依赖于精氨酸的Treg/Th 17细胞可塑性。迄今为止，动脉粥样硬化对Treg/Th 17平衡的影响尚不清楚。Th 17细胞在动脉粥样硬化形成中的Th 1优势应答中的作用尚未明确。我们最近的数据揭示了载脂蛋白E（Apoe-/-）小鼠中Th 17细胞的增加和IL-17 A的促动脉粥样硬化作用。我们的数据暗示了血浆来源的细胞因子在调节Treg/Th 17平衡中的功能。IFN 3 +IL-17 A + T细胞在Apoe-/-小鼠中的存在表明Th 17细胞保持可塑性并且可能与Th 1细胞合作。我们假设动脉粥样硬化疾病将Th 17/Treg细胞的相互平衡向Th 17细胞转移。这些Th 17细胞促进Th 1细胞归巢到动脉粥样硬化中，并与Th 1细胞一起在动脉粥样硬化形成期间提供协同免疫应答。目的1：动脉粥样硬化疾病在多大程度上改变了Treg/Th 17细胞的平衡，使其向Th 17细胞的生成转变？为了检查动脉粥样硬化形成中的Treg/Th 17相互调节，将来自Foxp-3 YFP-CreR 26 Y +/+和Foxp-3 YFP-CreR 26 Y-/-小鼠的初始T细胞（或天然或诱导性Treg）过继转移到C57 BL/6或Apoe-/-小鼠中;允许我们追踪先前是Treg或目前表达Foxp-3的细胞。将评估产生的供体Treg、Th 17细胞或从Treg转化为Th 17细胞的细胞的数量。我们将研究血浆细胞因子在调节Treg/Th 17平衡中的作用，并研究调节这种相互平衡的转录因子之间的相互作用。我们将证明，通过全反式维甲酸治疗，Treg/Th 17细胞平衡向Treg转移将减少主动脉炎症反应。目的2：证实Th 17和Th 1细胞在动脉粥样硬化形成中的协同反应。我们将使用Th 1细胞过继转移到Il 17 a-/-Apoe-/-和Apoe-/-小鼠中来检查IL-17依赖性的Th 1细胞归巢到胸腺中。我们将分析IL 17 a-/-Apoe-/-和Apoe-/-小鼠的免疫应答和Th 1趋化因子表达。接下来，我们将Th 1或Th 17或Th 1 + Th 17细胞过继转移到Apoe-/-小鼠中，以检查协同Th 1/Th 17应答在主动脉炎症中的作用。我们将通过将Th 17细胞过继转移到Apoe-/-小鼠中来鉴定Th 17重编程为IL-17+ IFN 3+或Th 1细胞的水平，并检查IFN 3 +IL-17+炎性细胞谱。这项研究具有创新性，因为Th 17与Th 1和Treg细胞在动脉粥样硬化中的相互作用尚未被描述。该提案利用了我们实验室中产生的独特的Foxp-3 YFP-CreR 26 Y小鼠和新的IL-17 A缺陷型Apoe-/-小鼠。我们的项目将提供关于IL-17 A参与动脉粥样硬化形成的新的机制数据，并突出Th 17细胞在这种疾病中的Th 1/Treg应答中的意想不到的作用。

DESCRIPTION (provided by applicant): Thelpers 1 (Th1) cells play a pro-atherogenic role, whereas regulatory T cells (Treg) demonstrate anti-inflammatory effects. The role of Th17 (CD4+IL-17+) cells in atherosclerosis remains controversial. Evidence suggests an existence of the cytokine-dependent Treg/Th17 cell plasticity. To date, the effects of atherosclerosis on the Treg/Th17 balance are unclear. The role of Th17 cells in the Th1- prevalent response in atherogenesis is not well defined. Our recent data reveals an increase of Th17 cells in apolipoprotein E (Apoe-/-) mice and a pro-atherogenic role of IL-17A. Our data implicates a function for plasma-derived cytokines in the regulation of the Treg/Th17 balance. The presence of IFN3+IL-17A+ T cells in Apoe-/- mice indicates that Th17 cells retain plasticity and may cooperate with Th1 cells. We hypothesize that atherosclerotic conditions shift the reciprocal Th17/Treg cell balance towards Th17 cells. These Th17 cells promote Th1 cell homing into aortas and together with Th1 cells provide a cooperative immune response during atherogenesis. Aim 1: To what extent do atherosclerotic conditions shift the balance of Treg/Th17 cells towards generation of Th17 cells? To examine the Treg/Th17 reciprocal regulation in atherogenesis, naive T cells (or natural or inducible Treg) from Foxp-3YFP-CreR26Y+/+ and Foxp-3YFP-CreR26Y-/- mice will be adoptively transferred into either C57BL/6 or Apoe-/- mice; allowing us to track cells that were previously Treg or currently express Foxp-3. The number of generated donor Treg, Th17 cells or cells converted from Treg to Th17 cells will be assessed. We will investigate the role of plasma cytokines in the regulation of Treg/Th17 balance and examine the interactions between transcription factors that regulate this reciprocal balance. We will show that shifting of the Treg/Th17 cell balance towards Treg via all-trans retinoic acid treatment will reduce the aortic inflammatory responses. Aim 2: To demonstrate a synergistic response of Th17 and Th1 cells in atherogenesis. We will examine IL-17-dependent homing of Th1 cells into aortas using adoptive transfer of Th1 cells into Il17a-/-Apoe-/- and Apoe-/- mice. We will analyze the immune response and Th1 chemokine expression in the aortas of Il17a-/-Apoe-/- and Apoe-/- mice. Next, we will adoptively transfer Th1 or Th17 or Th1+Th17 cells into Apoe-/- mice to examine a role of synergistic Th1/Th17 responses in the aortic inflammation. We will identify the levels of reprogramming of Th17 to IL-17+IFN3+ or Th1 cells by adoptive transfer of Th17 cells into Apoe-/- mice and examine IFN3+IL-17+ inflammatory cell profile. The proposed research is innovative, since the interaction of Th17 with Th1 and Treg cells in atherosclerosis has not been described. This proposal utilizes unique Foxp-3YFP-CreR26Y mice and new IL-17A-deficient Apoe-/- mice generated in our lab. Our project will provide new mechanistic data about IL-17A involvement in atherogenesis and highlight the unexpected role of Th17 cells in the Th1/Treg responses in this disease.