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: 7725827
• 负责人: MARKUS MOHRS
• 金额: $ 38.9万
• 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/7725827
• 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中的适应性宿主反应的特征在于： CD 4 + Th 2细胞及其标志性细胞因子IL-4的存在。Th 2细胞和IL-4与 对蠕虫寄生虫的保护性免疫反应，它们在某些免疫病理学中是有害的 例如抗原诱导的哮喘反应、特应性和变态反应。Th 2细胞与 然而，目前尚不清楚Th 2细胞是如何从幼稚CD 4 + T细胞发育而来的， 许多研究表明，IL-4 Ra介导的信号和IL-4是Th 2细胞所必需的， 然而，关于体外幼稚CD 4 + T细胞的发育，对体内这些过程知之甚少。这 主要是由于难以识别和追踪由IL-4表达定义的Th 2细胞。克服这些 局限性我们已经开发了双顺反子IL-4报告基因（4get）小鼠。与体外研究相比，我们的 初步数据显示，Th 2引发在感染IL-4 Ra-/- 4get的小鼠中惊人地有效。 鼠蠕虫H.多脑回因此，IL-4 R和IL-4对Th 2发育的作用是有争议的。 最近，我们已经产生了新的IL-4双报告小鼠（4get/KN 2），并揭示了IL-4的能力， 和IL-4的产生是不同的步骤。在这里，我们提出了一种新的模型，其中Th 2的发展和IL-4 生产发生在几个不同的，可识别的步骤：1。激活，2.差异化，3.膨胀，4. IL-4 生产，5。传播。在当前的应用中，我们将重新审视IL-4和IL-4 Ra介导的细胞因子的作用。 Th 2分化和IL-4产生的信号。我们 假设IL-4 R功能不需要使CD 4 + T细胞的Th 2启动成核，但在CD 4 + T细胞中起作用。 在这个模型的多个其他步骤中发挥作用。在目标1中，我们将分析在Th 2分化中的哪些步骤， 内源性T细胞群体响应于感染而受IL-4 R信号调节。在目标2中， 确定Th 2分化中的哪些步骤由直接介导的IL-4 R信号调节， 抗原特异性CD 4 + T细胞。我们将过继转移apTCR转基因CD 4 + T细胞并免疫 与同源抗原一起使用H.多脑回幼虫作为Th 2佐剂。在目标3中，我们将剖析 Th 2分化多步骤过程中选择性谱系的IL-4和IL-4 Ra表达我们将 产生在选择性细胞谱系中缺乏相应组分的各种骨髓嵌合体 并跟踪内源性T辅助细胞对感染的反应的发展。总体而言， 目的是揭示IL-4 R和IL-4调节Th 2发育的多个步骤的机制， vivo.这些见解对于设计针对性的激动性和拮抗性干预策略具有价值 IL-4 R和IL-4。