The interdependence between T and B cells in Th2 cell differentiation

描述（由申请人提供）：根据世界卫生组织，土壤传播的蠕虫寄生虫是最常见的获得性感染之一。这些感染引起强大的CD4+ T辅助细胞和B细胞反应。CD4+ T辅助细胞高度Th2极化并在再刺激时产生IL-4。伴随的B细胞反应的特点是血清中高浓度的2型免疫球蛋白IgG1和IgE。实验小鼠感染多回Heligmosomoides或Trichuris muris可诱导这些原型反应，是研究体内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CD4+ T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-4R1-/-小鼠在早期启动Th2细胞的分化，但与wt小鼠相比，它们的扩增和成熟被中止。引人注目的是，Th2反应缺陷伴随着B细胞反应几乎完全缺乏扩增和成熟。此外，IL-4R1-/-小鼠不能免受多回h.p ygyrus的回忆性感染。其次，与IL-4R1-/-小鼠一样，B细胞缺陷小鼠在感染多回H.或鼠t时也不能完全成熟初始Th2反应，也不能免受回忆感染的保护。总的来说，我们的初步数据表明，早期Th2细胞的发育是独立于B细胞和IL-4R1信号启动的，但不能进展和成熟。我们的中心假设是Th2细胞是B细胞反应的扩展和功能成熟所必需的，而B细胞反应反过来又对启动的Th2反应的完全扩展和功能成熟至关重要。我们假设CD4+ T细胞衍生的IL-4和B细胞的抗原呈递对于Th2细胞分化中T细胞和B细胞之间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验证这一假设，以解剖缺乏IL-4R1信号时B细胞的反应，以及在完全缺乏B细胞或B细胞选择性缺乏特定分子时产生的Th2反应。我们将测试在体外缺乏B细胞的情况下产生的Th2细胞的功能潜力，并将其过继转移到野生型宿主中。最后，我们将测试B细胞是否在野生型环境中启动Th2细胞的回忆功能中也起关键作用。我们相信，我们的研究将促进我们对Th2发展与相关B细胞反应相互依赖的理解。这些基本见解将与感染和疫苗接种以及特应性、哮喘和过敏性疾病中的Th2反应相关。与公共卫生相关的Th2细胞相关疾病折磨着全世界数十亿人，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.