T cell plasticity in atherosclerosis

描述（由申请人提供）：Thelpers 1 （Th1）细胞起促动脉粥样硬化作用，而调节性T细胞（Treg）具有抗炎作用。Th17 （CD4+IL-17+）细胞在动脉粥样硬化中的作用仍有争议。有证据表明存在依赖细胞因子的Treg/Th17细胞可塑性。迄今为止，动脉粥样硬化对Treg/Th17平衡的影响尚不清楚。Th17细胞在动脉粥样硬化中Th1-流行反应中的作用尚未明确。我们最近的数据揭示了载脂蛋白E （Apoe-/-）小鼠中Th17细胞的增加和IL-17A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/Th17平衡中的作用。Apoe-/-小鼠中IFN3+IL-17A+ T细胞的存在表明Th17细胞保持可塑性，并可能与Th1细胞合作。我们假设动脉粥样硬化条件将Th17/Treg细胞平衡向Th17细胞转移。这些Th17细胞促进Th1细胞归巢到主动脉，并与Th1细胞一起在动脉粥样硬化过程中提供协同免疫反应。目的1：动脉粥样硬化状况在多大程度上改变Treg/Th17细胞的平衡，使其倾向于生成Th17细胞？为了研究Treg/Th17在动脉粥样硬化中的相互调节作用，将foxp - 3yfp - creer26y +/+和foxp - 3yfp - creer26y -/-小鼠的幼稚T细胞（或天然或诱导的Treg）移入C57BL/6或Apoe-/-小鼠；使我们能够追踪以前是Treg或目前表达Foxp-3的细胞。将评估生成的供体Treg、Th17细胞或由Treg转化为Th17细胞的细胞的数量。我们将研究血浆细胞因子在调节Treg/Th17平衡中的作用，并研究调节这种互惠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将Treg/Th17细胞平衡向Treg方向转移将减少主动脉炎症反应。目的2：证明Th17和Th1细胞在动脉粥样硬化发生中的协同反应。我们将通过将Th1细胞过继转移到il - 17a-/-Apoe-/-和Apoe-/-小鼠体内来检测Th1细胞是否依赖il -17归巢进入主动脉。我们将分析il - 17a-/-Apoe-/-和Apoe-/-小鼠的免疫反应和Th1趋化因子的表达。接下来，我们将过继性地将Th1或Th17或Th1+Th17细胞转移到Apoe-/-小鼠体内，以研究协同Th1/Th17反应在主动脉炎症中的作用。我们将通过将Th17细胞过继转移到Apoe-/-小鼠中，确定Th17对IL-17+IFN3+或Th1细胞的重编程水平，并检查IFN3+IL-17+炎症细胞谱。这项研究具有创新性，因为Th17与Th1和Treg细胞在动脉粥样硬化中的相互作用尚未被描述。本研究采用独特的foxp - 3yfp - creer26y小鼠和我们实验室新生成的il - 17a缺陷Apoe-/-小鼠。我们的项目将提供IL-17A参与动脉粥样硬化形成的新机制数据，并强调Th17细胞在该疾病中Th1/Treg反应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.