Evolution of Mucosal B Cell Immunity: Novel Roles of IgT+ B Cells in the Control of Host-pathogen Interactions

粘膜 B 细胞免疫的进化：IgT B 细胞在控制宿主-病原体相互作用中的新作用

• 批准号: 1457282
• 负责人: Oriol Sunyer
• 金额: $ 63.2万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1457282&HistoricalAwards=false
• 关键词: Evolution; Mucosal; Cell; Immunity; Novel

The mucosal surfaces of vertebrates such as the gut and mouth are inhabited by resident bacteria and also continuously exposed to invading microbes. Throughout evolution, specific types of antibodies have become specialized to protect such mucosal sites. In mammals and birds, immunoglobulin A (IgA) predominates at mucosal surfaces, whereas IgG and IgM provide systemic protection. While fish were thought to be devoid of antibodies dedicated to defend mucosal areas throughout the body, fish with true bones (teleost fish) have been recently found to contain an antibody molecule that is specialized to defend for the skin and gut areas. However, very little is still known about the function of this molecule and the cells producing it. This project proposes further studies on this area which will bring new insights into the evolution of mucosal immunity and its role in host-pathogen interactions in primitive vertebrates. Mucosal areas of fish, including the gut, skin and gills, represent the main areas through which pathogens infect these species. On a broader level beyond new basic scientific knowledge, these studies will benefit society by contributing to the aquaculture and fishing industries. By better understanding how fish defend these mucosal surfaces better tools to combat fish diseases can be developed. Until recently it was thought that mucosal immunoglobulins evolved from tetrapod species. Breaking this paradigm, trout IgT was shown to be an immunoglobulin specialized in gut mucosal immunity and concurrently, a new B cell subset was described uniquely expressing IgT. These findings have led to hypothesize a key role for IgT in mucosal immunity supported by the large numbers of IgT+ B cells that accumulate at sites of infection in both the gut and the skin that are pathogen-specific immunoglobulin (IgT) responses. Curiously, the IgT+ B cells express the highest levels of IL-10 of any other leukocyte. IL-10 is a key anti-inflammatory cytokine. Based on the unanticipated high IL-10 producing capacity of IgT+ B cells, it is now hypothesized that these cells play novel immunoregulatory functions in both mucosal and systemic organs upon pathogenic challenge. As these cells are crucial for producing pathogen-specific mucosal IgT responses, it is also hypothesized that IgT+ B cells play a pivotal role in the control and/or clearance of pathogens in mucosal surfaces. Utilizing a novel IgT+ B cell-depletion fish model, the project presents aims to assess the mechanistic basis of the inflammatory and regulatory responses in the depleted fish upon pathogenic challenge. The pathogens chosen for this purpose infect either skin only, gut only or produce systemic infections. Thus the investigators will be able to evaluate the IgT+ B cell contribution to pathogen control and clearance in animals infected with the pathogens and they will use illumina high throughput transcriptome sequencing analysis following infection. These combined approaches will illuminate the role of IgT positive B cells in teleost fish with differing pathogenic challenges.

脊椎动物的肠道和口腔等粘膜表面是常驻细菌的栖息地，同时也不断暴露于入侵微生物中。在整个进化过程中，特定类型的抗体已经成为专门保护这些粘膜部位的抗体。在哺乳动物和鸟类中，免疫球蛋白A （IgA）在粘膜表面占主导地位，而IgG和IgM则提供全身保护。虽然鱼类被认为缺乏专门用于保护全身粘膜区域的抗体，但最近发现有真骨的鱼（硬骨鱼）含有一种专门用于保护皮肤和肠道区域的抗体分子。然而，对这种分子的功能和产生它的细胞所知甚少。本课题将在这一领域开展进一步的研究，为原始脊椎动物粘膜免疫的进化及其在宿主-病原体相互作用中的作用提供新的认识。鱼类的粘膜区域，包括肠道、皮肤和鳃，是病原体感染这些物种的主要区域。在新的基础科学知识之外的更广泛层面上，这些研究将通过对水产养殖业和渔业作出贡献而造福社会。通过更好地了解鱼类如何保护这些粘膜表面，可以开发出更好的工具来对抗鱼类疾病。直到最近，人们还认为粘膜免疫球蛋白是从四足动物进化而来的。打破这一范式，鳟鱼IgT被证明是一种专门参与肠道粘膜免疫的免疫球蛋白，同时，一个新的B细胞亚群被描述为唯一表达IgT。这些发现导致假设IgT在粘膜免疫中的关键作用，由大量的IgT+ B细胞支持，这些细胞积聚在肠道和皮肤的感染部位，这是病原体特异性免疫球蛋白（IgT）反应。奇怪的是，IgT+ B细胞表达的IL-10水平是其他白细胞中最高的。IL-10是一个关键的抗炎细胞因子。基于IgT+ B细胞意想不到的高IL-10生产能力，现在假设这些细胞在病原体攻击时在粘膜和全身器官中发挥新的免疫调节功能。由于这些细胞对产生病原体特异性粘膜IgT反应至关重要，因此也有假设认为IgT+ B细胞在控制和/或清除粘膜表面病原体方面发挥关键作用。利用一种新的IgT+ B细胞耗竭鱼模型，该项目旨在评估耗竭鱼在病原挑战下炎症和调节反应的机制基础。为此目的选择的病原体要么只感染皮肤，要么只感染肠道，要么产生全身感染。因此，研究人员将能够评估IgT+ B细胞对感染病原体的动物的病原体控制和清除的贡献，他们将在感染后使用illumina高通量转录组测序分析。这些结合的方法将阐明IgT阳性B细胞在具有不同致病挑战的硬骨鱼中的作用。