Epithelial TLR signaling and IgA production

描述(由申请人提供)： 一些研究表明，正常肠上皮细胞(IECs)表达Toll样受体，通过这些受体传递的信号可能在维持肠道内环境稳定方面发挥作用。为了测试上皮TLR信号在粘膜免疫反应中的作用，我们培育了在肠道上皮细胞中表达TLR4的转基因小鼠(V-TLR4小鼠)。通过IEC表达该转基因可以模拟Toll配体的信号传递，并促进一组特定的趋化因子和肿瘤坏死因子家族成员APRIL的表达。这些联合活动导致B细胞向固有层的募集增加，并增加了IgA向肠腔的分泌。肠上皮中TLR信号的增加导致肠腔中IgA的分泌增加，这表明存在一种以上皮为基础的机制，通过适当增加IgA水平来响应细菌或病毒的攻击。在这一应用中，我们的目标是了解这一机制的基本组成部分，并探讨上皮细胞中TLR信号的增加是增强还是抑制免疫反应。从这些研究中获得的知识可能有助于更好地理解TLR信号在上皮功能中的作用，并有助于开发更好的疫苗接种方法。具体地说，我们将1)确定肠道上皮中的结构性TLR信号促进趋化因子和IgA产生增加的机制，以及2)确定肠道上皮中的结构性TLR信号是否影响主动免疫和耐受。肠道内的细胞表达表面受体，这些受体可能会通知身体存在感染性病原体。为了测试这种受体在粘膜免疫反应中的作用，我们培育了具有大量这种受体的小鼠品系。我们发现，这些动物在肠道中分泌大量抗体。由于抗体的产生是免疫防御的关键组成部分，我们得出结论，这些受体在感染的免疫反应中发挥着关键作用。这项申请中提出的工作旨在了解这些受体产生的信号如何促进抗体产生，以及这些“工程”动物是否拥有更强大的免疫系统。来自这些研究的见解可能有助于开发更好的疫苗。

DESCRIPTION (provided by applicant): Several studies suggest that normal intestinal epithelial cells (IECs) express Toll like receptors and that signaling through these receptors may play a role in maintaining intestinal homeostasis. To test the role of epithelial TLR signaling in mucosal immune responses, we generated transgenic mice that express a constitutively active form of TLR4 in the intestinal epithelium (V-TLR4 mice). Expression of this transgene by IEC mimicked signaling by Toll ligands and promoted the expression of a select group of chemokines and the TNF family member APRIL. These combined activities resulted in increased recruitment of B cells to the lamina propria and increased secretion of IgA into the intestinal lumen. The observation that increased TLR signaling in the intestinal epithelium induces increased secretion of IgA in the intestinal lumen indicates the existence of a epithelium-based mechanism to respond to bacterial or viral challenges with an appropriate increase in the level of IgA. In this application we aim to understand the basic components of this mechanism and inquire if increased TLR signaling in the epithelium enhances or suppresses the immune response. Knowledge derived from these studies is likely to contribute to a better understanding of the role of TLR signaling in epithelial function and to the development of better vaccination approaches. Specifically we will 1) define the mechanisms whereby constitutive TLR signaling in the gut epithelium promotes increased production of chemokines and IgA and, 2) determine if constitutive TLR signaling in the gut epithelium affects active immunization and tolerance. Cells lining the intestine express surface receptors that may inform the body about the presence of infectious agents. To test the role of such receptors in mucosal immune responses, we generated strains of mice that have a large number of these receptors. We found that these animals secrete large amounts of antibodies in the intestine. As antibody production is a key component of the immune defense, we conclude that these receptors play a key role in the immune response to infection. The work presented in this application aims to understand how the signals elicited from these receptors promote antibody production and whether these "engineered" animals have stronger immune systems. Insights from these studies may contribute to development of better vaccines.