INNATE MECHANISMS OF REGULATION OF MEMORY TH17 CELL RESPONSES

调节记忆 TH17 细胞反应的先天机制

• 批准号: 10063467
• 负责人: Chandrashekhar Pasare
• 金额: $ 39.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063467
• 关键词: Adaptive Immune System; Affect; Autoimmune Diseases; Autoimmunity; Bacterial Infections; Binding; CASP1 gene; CD4 Positive T Lymphocytes; Cell Communication; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Cleaved cell; Complex; Data; Dendritic Cells; Development; Exposure to; Family; Genetic Transcription; Human; Immune response; Immune system; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune System; Instruction; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-12; Interleukin-17; Interleukin-18; Interleukin-6; Invaded; Investigation; Mediating; Memory; Molecular; Mucosal Immune System; Mus; Myeloid Cells; Natural Immunity; Nature; Pathway interactions; Pattern recognition receptor; Physiological; Play; Production; Receptor Activation; Receptor Signaling; Regulation; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Source; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Toll-like receptors; Transcript; Virulent; Work; adaptive immune response; adaptive immunity; chemokine; cytokine; cytosolic receptor; extracellular; fighting; in vivo; interleukin-22; macrophage; memory CD4 T lymphocyte; novel; pathogen; pathogenic microbe; receptor; response; targeted treatment

Project Summary The innate immune system has several families of pattern recognition receptors to detect invading pathogens and initiate inflammatory responses to rapidly eliminate the pathogen. The innate immune system also plays an instructive role in induction of adaptive immune responses against virulent pathogens. Toll-like receptors (TLR) are one such family of receptors and their activation in cells of the innate immune system, such as dendritic cells and macrophages, induces secretion of several pro-inflammatory cytokines such as IL-6, IL-12, TNFα, etc. Many of these cytokines play an important role in T cell activation and differentiation. TLR activation also leads to synthesis of a second family of cytokines comprised of IL-1 and IL-18 which are cleaved into active forms and secreted following activation of a different family of cytosolic receptors called NOD like receptors (NLRs). The cytokines IL-1 and IL-18 have major influence in directing T cell activation and differentiation and more importantly use the same signaling components as the TLR signaling pathway. It is becoming clear that IL-1 and IL-18 are the major players in innate control of adaptive immunity and the mechanisms by which they regulate T cell activation and differentiation are not completely understood. Our previous work has shown that IL-R mediated MyD88 dependent signaling is critical for Th17 lineage differentiation in systemic and mucosal immune systems. Th17 cells are crucial for fighting fungal and extracellular bacterial infections and have also been implicating in causing auto-immune diseases such as Rheumatoid Arthritis and Inflammatory Bowel Disease. It is therefore crucial to understand the cellular and molecular mechanisms by which these cells are regulated. In our new studies we have found that IL-1 plays a critical role in regulating effector functions of already primed Th17 memory T cells. We propose to build on these findings and gain a deeper understanding of how IL-1 regulates functioning of Th17 cells and elucidate the physiological significance of IL-1 mediated regulation of Th17 effector functions. In Aim 1, we will understand of the cellular and molecular mechanisms by which IL-1 is made during dendritic cell-memory Th17 cell interactions. In Aim 2, we will elucidate the signaling and molecular mechanisms by which IL-1R signaling in T cells impacts production of IL-17 and related family of cytokines. In Aim 3, we will use in vivo approaches to understand the importance of IL-1R signaling in memory Th17 cell function and examine the role of IL-1 in reactivation of pathogen specific memory Th17 cells as well as memory Th17 cells that cause auto-immunity . These studies will significantly advance our understanding of the role of IL-1 family of cytokines in regulation of CD4 T cell functions. Further more, unraveling the molecular mechanisms by which IL-1 family of cytokines regulate effector and memory T cell functions will not only enhance our understanding of immune responses against pathogens but will aid in development of targeted therapies to dampen inflammatory T cell responses.

项目摘要 先天免疫系统有几个模式识别受体家族来检测入侵的病原体。 并引发炎症反应，迅速消除病原体。先天免疫系统也扮演着 在诱导针对强毒病原体的获得性免疫反应方面具有指导作用。Toll样受体 (TLR)是这样一个受体家族，它们在先天性免疫系统的细胞中被激活，例如 树突状细胞和巨噬细胞，诱导几种促炎细胞因子的分泌，如IL-6，IL-12， 其中许多细胞因子在T细胞的活化和分化过程中起着重要的作用。TLR激活 还导致由IL-1和IL-18组成的第二个细胞因子家族的合成，这些细胞因子被裂解成 激活不同的胞浆受体家族NOD样后的活性形式和分泌 受体(NLRs)。细胞因子IL-1和IL-18在引导T细胞活化和 分化，更重要的是使用与TLR信号通路相同的信号成分。它是 越来越清楚的是，IL-1和IL-18是适应性免疫的先天控制的主要参与者，而 它们调节T细胞活化和分化的机制还不完全清楚。我们的 以往的工作表明，IL-R介导的MyD88依赖的信号转导对Th17谱系至关重要 系统和粘膜免疫系统的分化。Th17细胞对对抗真菌和 细胞外细菌感染，也与引起自身免疫性疾病有关，如 类风湿性关节炎和炎症性肠病。因此，了解细胞和 调控这些细胞的分子机制。在我们的新研究中，我们发现IL-1在 在调节已经启动的Th17记忆T细胞的效应器功能中起关键作用。我们建议在此基础上 这些发现加深了对IL-1如何调节Th17细胞功能的理解，并阐明了 IL-1介导的Th17效应功能调节的生理学意义在目标1中，我们将 树突状细胞记忆Th17过程中IL-1产生的细胞和分子机制 细胞间的相互作用。在目标2中，我们将阐明IL-1R信号转导的信号和分子机制 在T细胞中影响IL-17及相关细胞因子家族的产生。在目标3中，我们将使用活体方法 了解IL-1R信号在记忆Th17细胞功能中的重要性，并探讨IL-1在记忆Th17细胞功能中的作用。 病原体特异性记忆Th17细胞以及导致自身免疫的记忆Th17细胞的重新激活。 这些研究将极大地促进我们对IL-1家族细胞因子在调节中的作用的理解 对CD4T细胞功能的影响。此外，揭示了IL-1家族细胞因子的分子机制 调节效应器和记忆T细胞的功能不仅会增强我们对免疫反应的理解 抗病原体，但将有助于开发有针对性的治疗，以抑制炎症T细胞反应。