GUT INFLUENCES ON IMMUNE DEVELOPMENT IN EARLY LIFE

 性状（由申请方提供）：已观察到生命早期是发生致耐受性应答的重要时期。这个时间也与肠道微生物群的建立相关，这也是耐受性发展所必需的。然而，目前还不清楚为什么耐受性在生命早期建立得最好，以及微生物群如何对免疫系统产生影响。在这里，我展示了肠道常驻细菌在生命早期自发地从肠腔转移到肠系膜淋巴结。这一过程是正常发育的一部分，但这一现象的细节仍不清楚。成年小鼠可以通过使用抗生素诱导细菌移位来操纵，这需要杯状细胞相关抗原传代（GAP）和CX3CR1+抗原呈递细胞（APC）。在这项授权中，我将定义细菌易位发生在生命早期，什么物种易位，从哪里物种起源，以及哪些器官物种易位使用16S深度测序小鼠器官在整个生命早期。我还将研究早期生命中的细菌易位是否需要GAP和CX3CR1+ APC，类似于成年小鼠，以及GAP或CX3CR1+ APC的操作是否使用转基因小鼠和GAP的药理学操作破坏细菌易位。最后，我将使用流式细胞术和全身性炎症的迟发型超敏反应模型来评估细菌易位在调节性T细胞和全身耐受性发展中的作用。该项目的完成将定义在生命早期生理细菌易位的新过程，它是如何调节的，以及它对免疫系统有什么影响，提供洞察肠道微生物群如何有助于耐受性的发展，以及生命早期细菌易位的破坏对终身免疫应答的影响。

 DESCRIPTION (provided by applicant): It has been observed early life is an important time for the development of tolerogenic responses. This time is also correlated to the establishment of the intestinal microbiota, which is also necessary for the development of tolerance. However, it is unclear why tolerance is established best during early life and how the microbiota confers an effect on the immune system. Here I show gut resident bacteria spontaneously translocate from the intestinal lumen to the mesenteric lymph nodes during early life. This process occurs as part of normal development, yet the details of this phenomenon remain undefined. Adult mice can be manipulated through the use of antibiotics to induce bacterial translocation, which requires goblet-cell-associated antigen passages (GAPs) and CX3CR1+ antigen presenting cells (APCs). In this grant I will define when bacterial translocation occurs during early life, what species translocate, from where the species originate, and to which organs species translocate using 16S deep sequencing of murine organs throughout early life. I will also investigate if bacterial translocation during early life requires GAPs and CX3CR1+ APCs, similar to adult mice, and if manipulation of GAPs or CX3CR1+ APCs disrupt bacterial translocation using transgenic mice and pharmacological manipulation of GAPs. Finally, I will evaluate the role bacterial translocation has in the development of regulatory T cells and systemic tolerance using flow cytometry and a delayed type hypersensitivity model of systemic inflammation. Completion of this project will define the novel process of physiologic bacterial translocation during early lfe, how it is regulated and what effects it has on the immune system, providing insight into how the intestinal microbiota contributes to the development of tolerance and the effect disruption of bacterial translocation during early life has on lifelong immune responses.