The role of IL-4 and IL-4Ralpha in the multi-step process of Th2 development

IL-4 和 IL-4Ralpha 在 Th2 发育的多步骤过程中的作用

• 批准号: 7531051
• 负责人: MARKUS MOHRS
• 金额: $ 39.29万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-11-15 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531051
• 关键词: A Mouse; Adjuvant; Allergic Reaction; Animals; Antigens; Asthma; Attention; Bone Marrow; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Chimera organism; Competence; Complex; Cytokine Receptors; Data; Development; Helminths; Human; Hypersensitivity; Immune response; Immunity; Immunization; In Vitro; Infection; Interleukin-4; Intervention; Larva; Mediating; Medical; Modeling; Mouse Strains; Mus; Nematoda; Nematode infections; Nematospiroides dubius; Parasites; Parasitic nematode; Pathway interactions; Play; Population; Positioning Attribute; Process; Production; Publications; Reaction; Reporter; Research Design; Role; Signal Transduction; Soil; Source; T-Lymphocyte; Testing; Th2 Cells; Therapeutic Intervention; Transgenic Organisms; Work; airway hyperresponsiveness; atopy; base; cytokine; design; gastrointestinal; immunopathology; in vivo; insight; interest; mouse model; novel; research study; response; selective expression

Soil transmitted parasitic nematodes are world wide one of the most commonly acquired infections with multicellular parasites. The adaptive host response in humans and mice is characterized by the presence of CD4+ Th2 cells and their signature cytokine IL-4. Th2 cells and IL-4 are associated with protective immune responses against helminth parasites they are detrimental in certain immunopathologies such as antigen-induced asthmatic reactions, atopy and allergy. While Th2 cells are associated with nematode infections; however, it is not clear how Th2 cells develop from naive CD4+ T cells in response to infection/ Numerous studies have shown that IL-4Ra-mediated signals and IL-4 are required for the Th2 development of naive CD4+ T cells in vitro, however, very little is known about these processes in vivo. This is largely due to the difficulty to identify and track Th2 cells defined by IL-4 expression. To overcome these limitations we have developed bicistronic IL-4 reporter (4get) mice. In contrast to in vitro studies, our preliminary data show that Th2 priming occurs surprisingly efficient in IL4Ra-/- 4get mice infected with the murine helminth H. polygyrus. Thus, the role of IL-4R and IL-4 for Th2 development is controversial. Recently we have generated novel IL-4 dual-reporter mice (4get/KN2) and revealed that IL-4 competence and IL-4 production are distinct steps. Here we propose a novel model whereby Th2 development and IL-4 production occur in several distinct, identifiable steps: 1. activation, 2. differentiation, 3. expansion, 4. IL-4 production, 5. dissemination. In the current application we will revisit the role of IL-4 and IL-4Ra-mediated signals for Th2 differentiation and IL-4production using our unique dual-reporter mouse model. We hypothesize that IL-4R functions are not required to nucleate the Th2 priming of CD4+ T cells but play a role in multiple other steps of this model. In Aim 1 we will analyze which step(s) in Th2 differentiation of the endogenous T cell population are regulated by IL-4R signals in response to infection. In Aim 2 we will determine which step(s) in Th2 differentiation are regulated by IL-4R signals mediated directly on naive, antigen-specific CD4+ T cells. We will adoptively transfer apTCR transgenic CD4+ T cells and immunize with the cognate antigen using H. polygyrus larvae as a Th2 adjuvant. In Aim 3 we will dissect the role of IL-4 and IL-4Ra expression by selective lineages in the multi-step process of Th2 differentiation. We will generate various bone marrow chimeras which lack the respective components in selective cellular lineages and follow the development of the endogenous T helper response to infection. Collectively the proposed Aims will reveal the mechanism by which IL-4R and IL-4 regulate the multiple steps of Th2 development in vivo. These insights are valuable for designing agonistic and antagonistic intervention strategies targeting the IL-4R and IL-4.

土壤传播的寄生线虫是世界范围内最常见的获得性感染之一 多细胞寄生虫。人类和小鼠的适应性宿主反应的特征是 存在CD4+Th2细胞及其标志性细胞因子IL-4。Th2细胞和IL-4与 针对蠕虫寄生虫的保护性免疫反应在某些免疫病理中它们是有害的 如抗原诱导的哮喘反应、特应性和过敏性。而Th2细胞与 线虫感染；然而，目前尚不清楚Th2细胞是如何从原始的CD4+T细胞发育而来的 感染/大量研究表明，Th2需要IL-4ra介导的信号和IL-4 幼稚的CD4+T细胞在体外发育，然而，在体内对这些过程知之甚少。这 这在很大程度上是由于难以识别和跟踪由IL-4表达定义的Th2细胞。要克服这些障碍 局限性我们开发了双顺反子IL-4报告(4get)小鼠。与体外研究相比，我们的 初步数据显示，在感染了IL4Ra-/-4get的小鼠中，Th2的启动出奇地有效 小鼠蠕虫H多回。因此，IL-4R和IL-4在Th2形成中的作用是有争议的。 最近，我们创造了新的IL-4双报告小鼠(4get/Kn2)，并揭示了IL-4的活性 和IL-4的产生是不同的步骤。在这里，我们提出了一个新的模型，在这个模型中，Th2的发育和IL-4 生产发生在几个不同的、可识别的步骤中：1.激活，2.分化，3.扩张，4.IL-4 制作，5.传播。在当前的应用中，我们将重新审视IL-4和IL-4ra介导的作用 使用我们独特的双报告小鼠模型研究Th2分化和IL-4产生的信号。我们 假设IL-4R功能不是启动CD4+T细胞Th2启动所必需的，而是发挥作用 在此模型的多个其他步骤中扮演角色。在目标1，我们将分析在Th2分化中的哪一步(S) 内源性T细胞群受IL-4R信号的调节，以应对感染。在《目标2》中我们将 确定Th2分化的哪一步(S)受直接介导的IL-4R信号的调节， 抗原特异性的CD4+T细胞。我们将过继转移apTCR转基因的CD4+T细胞并免疫 以多脑回幼虫为Th2型佐剂，与同源抗原进行比较。在目标3中，我们将剖析 IL-4和IL-4ra在Th2多步分化过程中的选择性谱系表达我们会 产生各种骨髓嵌合体，这些嵌合体在选择性细胞谱系中缺乏各自的成分 并跟踪内源性T辅助细胞对感染反应的发展。所有建议的 AIMS将揭示IL-4R和IL-4调节Th2细胞发育的多个步骤的机制 活着。这些见解对于设计有针对性的激励性和拮抗性干预策略具有重要意义。 IL-4R和IL-4。