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，土壤传播的寄生虫是世界范围内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。多回Heligmosomoides polygyrus的小鼠实验感染诱导了这些原型反应，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一个非常强大的模型。Th2极化CD4+ T细胞提供单向B细胞帮助的功能已被广泛接受。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细胞的发育，但与wt小鼠相反，它们的扩增和成熟被中止。引人注目的是，有缺陷的Th2反应伴随着B细胞反应几乎完全没有扩增和成熟。此外，这些小鼠并不能免受多回h.p ygyrus的回忆性感染。其次，与IL-4R1-/-小鼠一样，B细胞缺陷小鼠也不能完全成熟地启动Th2反应，也不能免受回忆感染的保护。总的来说，我们的初步数据已经确定，早期Th2细胞的发育是独立于B细胞和IL-4R1介导的信号启动的，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介导信号时B细胞的反应和缺乏B细胞时产生的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wt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。项目的叙述

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.