Modulation of regulatory T- cell function by histamine and IL-6

组胺和 IL-6 调节调节性 T 细胞功能

• 批准号: 46295-2011
• 负责人: Hoskin, David
• 金额: $ 4.15万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=545001
• 关键词: Modulation; regulatory; cell; function; histamine

The immune system is responsible for defending against infection by disease-causing microorganisms. Specialized immune cells known as mast cells and regulatory T-cells are important components of this highly evolved defence mechanism. Although usually associated with allergy, mast cells also act as sentinel cells that warn of infection. Regulatory T-cells keep immune responses under tight control in order to prevent inadvertent immune cell-mediated damage to healthy tissues. My laboratory has recently shown that histamine released as a result of mast cell activation, which typically takes place during the early stages of infection, prevents regulatory T-cells from suppressing the activation of helper T-cells, which produce an array of chemical messengers called cytokines that guide the development of immune responses. This unique effect of histamine may allow regulatory T-cell function to be temporarily suspended in order to enhance the development of protective immunity. However, the mechanism by which histamine inhibits the function of regulatory T-cells is not well understood. Using a mouse model system, we will test the hypothesis that activation of signaling pathways associated with a particular histamine receptor on regulatory T-cells interferes with the ability of these regulatory T-cells to generate an immunosuppressive molecule known as adenosine, which has previously been shown to potently inhibit immune responses by helper T-cells. In addition, we will determine whether histamine also sensitizes regulatory T cells to a cytokine known as IL-6, which is commonly produced in response to infection and may also interfere with regulatory T-cell function. Mice are a model system that is commonly used to study the molecular basis of processes that are involved in the function of the human immune system. This fundamental research will add to our knowledge of the interactions that take place between mast cells and regulatory T-cells, and may suggest important new ways to selectively enhance the development of immune responses to disease-causing microorganisms and malignancy.

免疫系统负责抵御致病微生物的感染。专门的免疫细胞，如肥大细胞和调节性t细胞，是这种高度进化的防御机制的重要组成部分。尽管肥大细胞通常与过敏有关，但它也作为前哨细胞，对感染发出警告。调节性t细胞严格控制免疫反应，以防止无意的免疫细胞介导的健康组织损伤。我的实验室最近发现，肥大细胞激活（通常发生在感染的早期阶段）所释放的组胺会阻止调节性t细胞抑制辅助性t细胞的激活，辅助性t细胞会产生一系列被称为细胞因子的化学信使，引导免疫反应的发展。组胺的这种独特作用可能允许调节性t细胞功能暂时暂停，以增强保护性免疫的发展。然而，组胺抑制调节性t细胞功能的机制尚不清楚。使用小鼠模型系统，我们将验证与调节性t细胞上特定组胺受体相关的信号通路的激活干扰这些调节性t细胞产生称为腺苷的免疫抑制分子的能力的假设，腺苷先前已被证明可以有效抑制辅助性t细胞的免疫反应。此外，我们将确定组胺是否也使调节性T细胞对称为IL-6的细胞因子敏感，IL-6通常是在感染反应中产生的，也可能干扰调节性T细胞的功能。小鼠是一种模型系统，通常用于研究涉及人体免疫系统功能的过程的分子基础。这项基础研究将增加我们对肥大细胞和调节性t细胞之间发生的相互作用的认识，并可能为选择性地增强对致病微生物和恶性肿瘤的免疫反应的发展提供重要的新途径。