The interdependence between T and B cells in Th2 cell differentiation

描述(申请人提供)：根据世界卫生组织的说法，土壤传播的蠕虫寄生虫是最常见的感染之一。这些感染激发了强大的CD4T辅助细胞和B细胞反应。CD4T辅助细胞高度Th2极化，在重新刺激时产生IL-4。伴随的B细胞反应的特征是血清中2型免疫球蛋白IgG1和IgE浓度较高。小鼠感染小鼠的蠕虫寄生虫多回螺旋体或鞭虫引起这些原型反应，是在体内研究Th2发育、IL-4产生和2型B细胞反应的基本原理的非常强大的模型。Th2极化的CD4T细胞提供单向B细胞帮助的功能是众所周知的。然而，Th2分化和2型B细胞反应相互依赖发展的可能性几乎没有受到关注。我们的初步数据提供了两个关键发现。首先，IL-4R1-/-小鼠早期启动Th2细胞的分化，但与wt小鼠相比，其扩张和成熟被中止。值得注意的是，缺陷的Th2反应伴随着几乎完全缺乏B细胞反应的扩张和成熟。此外，IL-4R1-/-小鼠不能免受多回H。其次，与IL-4R1-/-小鼠一样，B细胞缺陷小鼠在感染多脑回或T细胞时也无法完全成熟启动的Th2反应，也不能免受Recall感染的保护。总而言之，我们的初步数据表明，Th2细胞的早期发育独立于B细胞和IL-4R1信号而启动，但未能进展和成熟。我们的中心假设是，Th2细胞是B细胞应答的扩增和功能成熟所必需的，而B细胞应答又是启动Th2应答的充分扩增和功能成熟的关键。我们推测CD4T细胞来源的IL-4和B细胞的抗原提呈对于T细胞和B细胞在Th2细胞分化过程中的相互依赖至关重要。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检验这一假设，以剖析在没有IL-4R1信号的情况下B细胞的反应，以及在完全没有B细胞或选择性地缺乏特定分子的B细胞的情况下产生的Th2反应。我们将在体外测试在没有B细胞的情况下产生的Th2细胞的功能潜力，以及过继转移到野生型宿主时的功能潜力。最后，我们将测试在野生型环境中启动的Th2细胞的回忆功能中，B细胞是否也是关键的。我们相信，我们的研究将促进我们对Th2发育与相关的B细胞反应相互依赖的理解。这些基本见解将在感染和疫苗接种以及特应性、哮喘和过敏性疾病的背景下与Th2反应相关。与公共卫生有关的Th2细胞相关疾病困扰着全球数十亿人，仅在美国就有数百万人。了解Th2细胞分化的基本机制是开发更有效的疫苗和改善哮喘、过敏性和特应性疾病的先决条件。

DESCRIPTION (provided by applicant): Soil transmitted helminth parasites are one of the most commonly acquired infections according to the WHO. These infections elicit robust CD4+ T helper cell 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 parasites Heligmosomoides polygyrus or Trichuris muris induce these prototypic responses and are exceptionally powerful models 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 well known. However, the possibility that Th2 differentiation and type 2 B cell responses develop in interdependence has received little attention. Our preliminary data provide two key findings. First, IL-4R1-/- mice initiate the differentiation 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 lack of the expansion and maturation of the B cell response. Moreover, IL-4R1-/- 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 upon infection with H. polygyrus or T. muris and are also not protected from a recall infection. Collectively our preliminary data have shown that early Th2 cell development is initiated independently of B cells and IL-4R1 signals but fails to progress and mature. It is our central hypothesis that Th2 cells are required for the expansion and functional maturation of a B cell response which in turn is critical for the full expansion and functional 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 signals and the Th2 response generated either in the complete absence of B cells or B cell selectively lacking specific molecules. We will test the functional potential of Th2 cells generated in the absence of B cells in vitro and upon adoptive transfer into wild type 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 with 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. PUBLIC HEALTH RELEVANCE 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.