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: 9246987
• 负责人: Chandrashekhar Pasare
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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/9246987
• 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; 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; Microbe; Molecular; Mus; Myeloid Cells; Natural Immunity; Nature; Pathogenicity; 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; novel; pathogen; 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家族的模式识别受体来检测入侵的病原体 并引发炎症反应以迅速消除病原体。先天免疫系统也发挥作用 在诱导针对毒性病原体的适应性免疫应答中的指导作用。toll样受体 (TLR)是这样的受体家族之一，并且它们在先天免疫系统的细胞中活化，例如 树突状细胞和巨噬细胞诱导几种促炎细胞因子如IL-6，IL-12， 这些细胞因子中的许多在T细胞活化和分化中起重要作用。TLR活化 也导致由IL-1和IL-18组成的第二家族细胞因子的合成， 活性形式，并在称为NOD样的不同胞质受体家族激活后分泌 受体（NLR）。细胞因子IL-1和IL-18在指导T细胞活化和活化中具有主要影响。 分化，更重要的是使用与TLR信号传导途径相同的信号传导组分。是 越来越清楚的是，IL-1和IL-18是获得性免疫的先天控制的主要参与者， 它们调节T细胞活化和分化的机制还不完全清楚。我们 以前的工作已经表明，IL-R介导的MyD 88依赖性信号传导对于Th 17谱系是关键的 在全身和粘膜免疫系统中的分化。Th 17细胞对于对抗真菌和 细胞外细菌感染，并且还涉及引起自身免疫性疾病， 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在体内起着重要的作用。 在调节已经引发的Th 17记忆T细胞的效应子功能中起关键作用。我们建议， 这些发现，并获得更深入的了解IL-1如何调节Th 17细胞的功能，并阐明 IL-1介导的调节Th 17效应子功能的生理意义。在目标1中，我们 了解树突状细胞记忆Th 17过程中产生IL-1的细胞和分子机制 细胞相互作用在目标2中，我们将阐明IL-1 R信号转导的信号转导和分子机制， 在T细胞中，IL-17和相关细胞因子家族的产生受到影响。在目标3中，我们将使用体内方法 了解IL-1 R信号在记忆Th 17细胞功能中的重要性，并检查IL-1在记忆Th 17细胞功能中的作用。 病原体特异性记忆Th 17细胞以及引起自身免疫的记忆Th 17细胞的再活化。 这些研究将极大地促进我们对IL-1家族细胞因子在调节 CD 4 T细胞功能进一步阐明了IL-1家族细胞因子在细胞内表达的分子机制， 调节效应和记忆T细胞功能不仅可以增强我们对免疫反应的理解， 但将有助于开发靶向治疗以抑制炎症T细胞反应。