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

• 批准号: 7881631
• 负责人: MARKUS MOHRS
• 金额: $ 41.88万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881631
• 关键词: Adoptive Transfer; Allergic; Animals; Antibodies; Antigen Presentation; Antigens; Attention; B-Cell Development; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; Cell Differentiation process; Collaborations; Data; Defect; Development; Disease; Employee Strikes; Environment; Helminths; Helper-Inducer T-Lymphocyte; Human; IgE; IgG1; IgG4; Immunoglobulin Class Switching; Immunoglobulins; In Vitro; Individual; Infection; Interleukin-4; Intestines; Linear Models; Mediating; Memory; Microscopy; Modeling; Mus; Nematoda; Nematospiroides dubius; Parasites; Performance; Phenotype; Play; Population; Production; Reporter; Role; Serum; Signal Transduction; Soil; Source; Staging; Surface; T-Lymphocyte; Testing; Th2 Cells; Trichuris; Vaccination; Vaccines; gastrointestinal; in vivo; insight; lymph nodes; public health relevance; research study; response

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.

描述（由申请人提供）：据世界卫生组织称，土壤传播的蠕虫寄生虫是最常见的感染之一。这些感染引发强烈的 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 2 型免疫球蛋白 IgG1 和 IgE 血清浓度高。用小鼠蠕虫寄生虫 Heligmosomoides polygyrus 或 Trichuris muris 实验性感染小鼠可诱导这些原型反应，并且是研究体内 Th2 发育、IL-4 产生和 2 型 B 细胞反应基本原理的异常强大的模型。 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 细胞反应相互依赖地发展的可能性却很少受到关注。我们的初步数据提供了两个关键发现。首先，IL-4R1-/-小鼠很早就启动了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展和成熟。此外，IL-4R1-/- 小鼠不能免受 H. polygyrus 的召回感染。其次，与 IL-4R1-/- 小鼠一样，B 细胞缺陷小鼠在感染多回菌或鼠 T. 后也无法完全成熟启动 Th2 反应，并且也无法免受回忆感染。总的来说，我们的初步数据表明，早期 Th2 细胞发育的启动独立于 B 细胞和 IL-4R1 信号，但无法进展和成熟。我们的中心假设是，B 细胞反应的扩展和功能成熟需要 Th2 细胞，而 B 细胞反应反过来对于启动的 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性至关重要。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 细胞反应，以及在完全没有 B 细胞或 B 细胞选择性缺乏特定分子的情况下产生的 Th2 反应。我们将测试在体外缺乏 B 细胞的情况下以及过继转移至野生型宿主后产生的 Th2 细胞的功能潜力。最后，我们将测试 B 细胞在野生型环境中引发的 Th2 细胞的回忆功能中是否也至关重要。我们相信，我们的研究将增进我们对 Th2 发育与相关 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、哮喘和过敏性疾病背景下的 Th2 反应相关。公共卫生相关性 Th2 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 Th2 细胞分化的基本机制是开发更有效的疫苗以及改善哮喘、过敏和特应性疾病的先决条件。