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The interdependence between T and B cells in Th2 cell differentiation

Th2细胞分化中T细胞和B细胞之间的相互依赖性

基本信息

批准号：
8282924
负责人：
MARKUS MOHRS
金额：
$ 41.46万
依托单位：
TRUDEAU INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Soil transmitted helminth parasites are one of the most commonly acquired infections and world wide according to the WHO. These infections elicit robust CD4+ T helper and B cell responses. The CD4+ T helper cells are highly Th2 polarized and produce IL-4 upon restimulation. The accompanying B cell response is characterized by high serum concentrations of the type 2 immunoglobulins IgG1 and IgE. Experimental infection of mice with the murine helminth parasite Heligmosomoides polygyrus induces these prototypic responses and is an exceptionally powerful model to study fundamental principles of Th2 development, IL-4 production and type 2 B cell responses in vivo. The function of Th2 polarized CD4+ T cells to provide unidirectional B cell help is widely accepted. However, the possibility that Th2 differentiation and type 2 B cell response develop in interdependence has received little attention. Our preliminary data provide two key findings. First, IL-4R1-/- mice initiate the development of Th2 cells early on, but in contrast to wt mice, their expansion and maturation is aborted. Strikingly, the defective Th2 response is accompanied by the almost complete absence of expansion and maturation of the B cell response. Moreover, these mice are not protected from a recall infection with H. polygyrus. Secondly, like IL-4R1-/- mice, B cell-deficient mice also fail to fully mature an initiated Th2 response and are also not protected from a recall infection. Collectively our preliminary data have established that early Th2 cell development is initiated independently of B cells and IL-4R1- mediated signals but fails to progress and mature. It is our central hypothesis that Th2 cells are required for the expansion and maturation of a B cell response which is in turn critical for the full expansion and maturation of the initiated Th2 response. We hypothesize that CD4+ T cell-derived IL-4 and antigen presentation by B cells are critical for the interdependence between T cells and B cells in Th2 cell differentiation. We will test this hypothesis by using a unique set of IL-4 reporter mice and mixed bone marrow chimeric mice to dissect the B cell response in the absence of IL-4R1-mediated signals and the Th2 response generated in the absence of B cells. We will test the functional potential of Th2 cells generated in the absence of B cells in vitro and upon adoptive transfer into wt hosts. Finally we will test whether B cells are also critical during the recall function of Th2 cells primed in a wild-type environment. We are convinced that our studies will advance our understanding of Th2 development in interdependence to the associated B cell response. These fundamental insights will be relevant for Th2 responses in the context of infection and vaccination as well as atopic, asthmatic, and allergic disorders. Project Narrative Th2 cell-associated diseases afflict billions of people world wide and millions of individuals in the US alone. Understanding the fundamental mechanisms of Th2 cell differentiation is a prerequisite for the development of more efficient vaccines and the amelioration of asthmatic, allergic, and atopic disorders.

描述（由申请人提供）：根据WHO，土壤传播蠕虫寄生虫是最常见的获得性感染之一，在世界范围内。这些感染引起强烈的CD 4 + T辅助细胞和B细胞应答。CD 4 + T辅助细胞是高度Th 2极化的，并在再刺激时产生IL-4。伴随的B细胞应答的特征在于2型免疫球蛋白IgG 1和IgE的高血清浓度。用鼠蠕虫寄生虫Heligmosomoides polygyrus实验性感染小鼠诱导这些原型应答，并且是研究体内Th 2发育、IL-4产生和2型B细胞应答的基本原理的非常有效的模型。Th 2极化的CD 4 + T细胞提供单向B细胞帮助的功能被广泛接受。然而，Th 2分化和2型B细胞应答相互依赖发展的可能性很少受到关注。我们的初步数据提供了两个关键发现。首先，IL-4 R1-/-小鼠早期启动Th 2细胞的发育，但与野生型小鼠相反，它们的扩增和成熟被中止。引人注目的是，缺陷性Th 2应答伴随着B细胞应答的扩增和成熟的几乎完全缺失。此外，这些小鼠不能免受H.多脑回其次，与IL-4 R1-/-小鼠一样，B细胞缺陷型小鼠也不能使起始的Th 2应答完全成熟，并且也不能免于回忆感染。总体而言，我们的初步数据已经确定，早期Th 2细胞的发育独立于B细胞和IL-4 R1介导的信号启动，但未能进展和成熟。我们的中心假设是，Th 2细胞是B细胞应答的扩增和成熟所必需的，而这又是启动的Th 2应答的完全扩增和成熟的关键。我们推测，CD 4 + T细胞来源的IL-4和抗原呈递的B细胞之间的相互依赖性T细胞和B细胞在Th 2细胞分化的关键。我们将通过使用一组独特的IL-4报告小鼠和混合骨髓嵌合小鼠来分析在不存在IL-4 R1介导的信号的情况下的B细胞应答和在不存在B细胞的情况下产生的Th 2应答来检验这一假设。我们将测试在体外不存在B细胞的情况下以及过继转移到野生型宿主中时产生的Th 2细胞的功能潜力。最后，我们将测试B细胞是否在野生型环境中引发的Th 2细胞的回忆功能期间也是关键的。我们相信，我们的研究将促进我们的理解Th 2的发展相互依存的相关B细胞的反应。这些基本的见解将是相关的感染和疫苗接种以及特应性，哮喘和过敏性疾病的背景下的Th 2应答。项目叙述 Th 2细胞相关疾病困扰着全世界数十亿人，仅在美国就有数百万人。了解Th 2细胞分化的基本机制是开发Th 2细胞的先决条件。更有效的疫苗和哮喘、过敏和特应性疾病的改善。