T cell plasticity in atherosclerosis

动脉粥样硬化中的 T 细胞可塑性

• 批准号: 8644304
• 负责人: Elena V Galkina
• 金额: $ 35.16万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644304
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Apolipoprotein E; Arteries; Atherosclerosis; B-Lymphocytes; CCL20 gene; CXCL10 gene; Cells; Chronic Disease; Data; Development; Disease; Environment; Equilibrium; Event; Generations; Growth; Homing; Immune; Immune response; Immunoglobulins; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-1; Interleukin-17; Interleukin-6; Lamina Propria; Maintenance; Molecular Profiling; Mus; Pattern; Plasma; Play; Prevention; Regulation; Regulatory T-Lymphocyte; Research; Role; Spleen; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tretinoin; aged; atherogenesis; cell motility; chemokine; cytokine; innovation; neutralizing antibody; neutrophil; novel strategies; public health relevance; response; synergism; transcription factor

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.

描述(申请人提供)：辅助者1(Th1)细胞发挥促动脉粥样硬化的作用，而调节性T细胞(Treg)则显示抗炎作用。Th17(CD4+IL-17+)细胞在动脉粥样硬化中的作用仍存在争议。有证据表明存在细胞因子依赖的Treg/Th17细胞可塑性。到目前为止，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形成中Th1流行反应中的作用尚不清楚。我们最近的数据显示，载脂蛋白E(APOE-/-)小鼠的Th17细胞增加，IL-17A具有促动脉粥样硬化的作用。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-/-小鼠体内存在IFN3+IL-17A+T细胞，提示Th17细胞具有可塑性，可能与Th1细胞协同作用。我们假设动脉粥样硬化使Th17/Treg细胞的平衡向Th17细胞转移。这些Th17细胞促进Th1细胞归巢到动脉中，并与Th1细胞一起在动脉粥样硬化形成过程中提供协同免疫反应。目的1：动脉粥样硬化在多大程度上改变了Treg/Th17细胞的平衡，使其向Th17细胞的生成倾斜？为了研究Treg/Th17在动脉粥样硬化形成中的相互调节，来自FoxP-3YFP-CreR26Y+/+和FoxP-3YFP-CreR26Y-/-小鼠的原始T细胞(或自然或诱导的Treg)将被过继转移到C57BL/6或APOE-/-小鼠中；使我们能够追踪以前是Treg或目前表达FoxP-3的细胞。将评估产生的供体Treg、Th17细胞或从Treg转化为Th17细胞的细胞数量。我们将研究血浆细胞因子在调节Treg/Th17平衡中的作用，并检查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使Treg/Th17细胞平衡向Treg偏移，将减少主动脉炎症反应。目的2：探讨Th17和Th1细胞在动脉粥样硬化形成中的协同作用。我们将通过将Th1细胞过继转移到IL17A-/-APOE-/-和APOE-/-小鼠体内，研究依赖于IL-17的Th1细胞在主动脉中的归巢。我们将分析IL17A-/-APOE-/-和APOE-/-小鼠的免疫反应和Th1趋化因子在主动脉中的表达。接下来，我们将过继地将Th1或Th17或Th1+Th17细胞转移到APOE-/-小鼠体内，以检测Th1/Th17协同反应在主动脉炎症中的作用。我们将通过过继将Th17细胞转移到APOE-/-小鼠体内来鉴定Th17细胞重编程为IL-17+IFN3+或Th1细胞的水平，并检测IFN3+IL-17+炎症细胞的特征。这项拟议的研究是创新的，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。该方案利用了独特的FoxP-3YFP-CreR26Y小鼠和我们实验室培育的新的IL-17A缺陷APOE-/-小鼠。我们的项目将提供有关IL-17A参与动脉粥样硬化形成的新的机制数据，并强调Th17细胞在Th1/Treg反应中意想不到的作用。