T cell plasticity in atherosclerosis

动脉粥样硬化中的 T 细胞可塑性

• 批准号: 8257890
• 负责人: Elena V Galkina
• 金额: $ 35.88万
• 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/8257890
• 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; 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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is an inflammatory chronic disease of the wall of large- and medium-sized arteries. This study will focus on the regulation of the reciprocal balance between suppressor T regulatory cells and pro- inflammatory Th17 cells, and synergistic effects of Th1 and Th17 cells in the development and progression of atherosclerosis. Anticipated results will help to understand the role of different T cell subsets and their reciprocal regulation in the immune response during atherosclerosis and will facilitate new approaches towards the prevention and treatment of the disease.

描述（由申请人提供）：Thelpers 1 (Th1) 细胞发挥促动脉粥样硬化作用，而调节性 T 细胞 (Treg) 则表现出抗炎作用。 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性 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形成中 Th1 普遍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 细胞的增加以及 IL-17A 的促动脉粥样硬化作用。我们的数据表明血浆来源的细胞因子在调节 Treg/Th17 平衡中发挥作用。 Apoe-/-小鼠中IFN3+IL-17A+ T细胞的存在表明Th17细胞保留了可塑性并且可能与Th1细胞合作。我们假设动脉粥样硬化状况使 Th17/Treg 细胞的相互平衡转向 Th17 细胞。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形成过程中提供协同免疫反应。目标 1：动脉粥样硬化状况在多大程度上使 Treg/Th17 细胞的平衡转向 Th17 细胞的产生？为了检查动脉粥样硬化形成中的 Treg/Th17 相互调节，来自 Foxp-3YFP-CreR26Y+/+ 和 Foxp-3YFP-CreR26Y-/- 小鼠的幼稚 T 细胞（或天然或诱导型 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 或当前表达 Foxp-3 的细胞。将评估生成的供体 Treg、Th17 细胞或从 Treg 细胞转化为 Th17 细胞的细胞的数量。我们将研究血浆细胞因子在 Treg/Th17 平衡调节中的作用，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，通过全反式视黄酸治疗将 Treg/Th17 细胞平衡转向 Treg 将减少主动脉炎症反应。目标 2：证明 Th17 和 Th1 细胞在动脉粥样硬化形成中的协同反应。我们将通过将 Th1 细胞过继转移至 Il17a-/-Apoe-/- 和 Apoe-/- 小鼠体内来检查 Th1 细胞依赖 IL-17 归巢至主动脉的情况。我们将分析 Il17a-/-Apoe-/- 和 Apoe-/- 小鼠主动脉中的免疫反应和 Th1 趋化因子表达。接下来，我们将 Th1 或 Th17 或 Th1+Th17 细胞过继转移至 Apoe-/- 小鼠体内，以研究 Th1/Th17 协同反应在主动脉炎症中的作用。我们将通过将 Th17 细胞过继转移至 Apoe-/- 小鼠体内，确定 Th17 重编程为 IL-17+IFN3+ 或 Th1 细胞的水平，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。该提案利用了我们实验室产生的独特的 Foxp-3YFP-CreR26Y 小鼠和新的 IL-17A 缺陷型 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机制数据，并强调 Th17 细胞在该疾病的 Th1/Treg 反应中发挥的意想不到的作用。 公共卫生相关性：动脉粥样硬化是大中型动脉壁的一种慢性炎症性疾病。本研究将重点关注抑制性T调节细胞和促炎性Th17细胞之间的相互平衡调节，以及Th1和Th17细胞在动脉粥样硬化发生和进展中的协同作用。预期结果将有助于了解不同 T 细胞亚群的作用及其在动脉粥样硬化期间免疫反应中的相互调节，并将促进预防和治疗该疾病的新方法。