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: 7184468
• 负责人: MARKUS MOHRS
• 金额: $ 39.94万
• 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/7184468
• 关键词: A Mouse; Adjuvant; Allergic Reaction; Animals; Antigens; Appendix; 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; World Health Organization; airway hyperresponsiveness; atopy; base; cytokine; design; gastrointestinal; immunopathology; in vivo; insight; interest; mouse model; novel; research study; response; selective expression

DESCRIPTION (provided by applicant): Soil transmitted parasitic nematodes are world wide one of the most commonly acquired infections with multi-cellular 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-4 production 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.

描述（由申请人提供）：土壤传播的寄生线虫是世界范围内最常见的多细胞寄生虫感染之一。人类和小鼠中的适应性宿主应答的特征在于存在CD 4 + Th 2细胞及其标志性细胞因子IL-4。Th 2细胞和IL-4与对抗蠕虫寄生虫的保护性免疫应答相关，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、特应性和过敏。虽然Th 2细胞与线虫感染相关;然而，尚不清楚Th 2细胞如何响应于感染而从初始CD 4 + T细胞发育。 大量研究表明，IL-4 Ra介导的信号和IL-4是体外幼稚CD 4 + T细胞Th 2发育所必需的，然而，对这些体内过程知之甚少。这主要是由于难以识别和跟踪由IL-4表达定义的Th 2细胞。为了克服这些限制，我们开发了双顺反子IL-4报告基因（4get）小鼠。与体外研究相反，我们的初步数据表明，Th 2启动在感染鼠蠕虫H的IL 4 Ra-/- 4get小鼠中发生惊人的有效性。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的生产是不同的步骤。在这里，我们提出了一个新的模型，其中Th 2的发展和IL-4的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产生，5.传播。在本申请中，我们将使用我们独特的双报告小鼠模型重新审视IL-4和IL-4 Ra介导的信号对于Th 2分化和IL-4产生的作用。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，但在该模型的多个其他步骤中发挥作用。在目的1中，我们将分析内源性T细胞群体的Th 2分化中的哪些步骤由IL-4 R信号响应于感染来调节。在目标2中，我们将确定Th 2分化中的哪些步骤由直接介导于幼稚抗原特异性CD 4 + T细胞上的IL-4 R信号调节。我们将过继转移apTCR转基因CD 4 + T细胞，并使用H.多脑回幼虫作为Th 2佐剂。在目的3中，我们将通过选择性谱系来剖析IL-4和IL-4 Ra表达在Th 2分化的多步骤过程中的作用。我们将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相应的成分，并跟踪内源性T辅助细胞对感染的反应的发展。总的来说，所提出的目的将揭示IL-4 R和IL-4调节体内Th 2发育的多个步骤的机制。这些见解对于设计针对IL-4 R和IL-4的激动性和拮抗性干预策略是有价值的。