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

基本信息

批准号：
7989122
负责人：
MARKUS MOHRS
金额：
$ 40.67万
依托单位：
TRUDEAU INSTITUTE, INC.
依托单位国家：
美国
项目类别：
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/7989122
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

项目摘要

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上最常见的感染之一多细胞寄生虫。人类和小鼠的自适应宿主反应的特征是 CD4+ Th2细胞的存在及其特征性细胞因子IL-4。 Th2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有害例如抗原诱导的哮喘反应，特应性和过敏。而Th2细胞与线虫感染；但是，尚不清楚Th2细胞如何从幼稚的CD4+ T细胞中发展为感染/众多研究表明，TH2需要IL-4RA介导的信号和IL-4 然而，在体外的这些过程中，幼稚的CD4+ T细胞的发展知之甚少。这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。克服这些我们已经开发了双科经IL-4记者（4get）小鼠的局限性。与体外研究相反，我们初步数据表明，Th2启动在IL4RA - / - 4get小鼠感染的效率令人惊讶鼠蠕虫h。多埃及。因此，IL-4R和IL-4在Th2发育中的作用是有争议的。最近，我们产生了新型的IL-4双重孢子小鼠（4get/kn2），并揭示了IL-4能力 IL-4生产是不同的步骤。在这里，我们提出了一个新型模型，通过TH2开发和IL-4 生产以几个不同的可识别步骤发生：1。激活，2。分化，3。扩展，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-4RA介导的作用使用我们唯一的双重变形蛋白小鼠模型的Th2分化和IL-4生产的信号。我们假设IL-4R函数不需要成核CD4+ T细胞的Th2启动，而是发挥作用在该模型的其他多个步骤中的作用。在AIM 1中，我们将分析TH2分化的哪个步骤内源性T细胞群受到感染的响应，由IL-4R信号调节。在目标2中，我们将确定TH2分化中的哪个步骤由直接介导的IL-4R信号调节，直接介导抗原特异性CD4+ T细胞。我们将过渡地转移APTCR转基因CD4+ T细胞并免疫使用同源抗原使用h. polygyrus幼虫作为Th2辅助物。在AIM 3中，我们将剖析在Th2分化的多步骤过程中，通过选择性谱系的IL-4和IL-4RA表达。我们将产生各种骨髓嵌合体，这些嵌合在选择性细胞谱系中缺乏各个组成部分并遵循内源性T助手对感染的反应的发展。共同提议目的将揭示IL-4R和IL-4调节Th2发展的多个步骤的机制体内。这些见解对于设计针对的激动和对抗干预策略很有价值 IL-4R和IL-4。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intestinal helminth infection impacts the systemic distribution and function of the naive lymphocyte pool.

DOI：
10.1038/mi.2016.127
发表时间：
2017-09
期刊：
Mucosal immunology
影响因子：
8
作者：
King IL;Mohrs K;Meli AP;Downey J;Lanthier P;Tzelepis F;Fritz JH;Tumanov AV;Divangahi M;Leadbetter EA;Mohrs M
通讯作者：
Mohrs M

Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo.