Investigate the impact of physiological microbial exposure on regulatory T cell-mediated immune regulation

严格的生物遏制防止实验室小鼠感染自然病原体，并允许 研究人员以可靠和可重复的方式进行动物实验。然而，这种特定的 无病原体(SPF)小鼠不一定要模拟自然界中发生的免疫反应，这可能 导致临床前研究和人体临床试验之间经常被报道的脱节。尽管 通过对SPF小鼠的研究，生物医学研究中的许多关键进展成为可能， 现在有令人信服的证据表明，微生物或病毒的经历可以极大地影响免疫病理生理学。在……里面 在过去的二十年里，调节性T(Treg)细胞已经成为一种专门的免疫群体，对 免疫反应的负性调节。考虑到Treg细胞的动态平衡和功能 受到不同组织环境中存在的独特信号的极大影响，可以想象 目前实验室环境外的微生物暴露可能会严重影响Treg细胞及其能力 只是为了建立对‘’自身‘’或无害的外来抗原的免疫耐受，而且也为了保持在 检查效应器对病原体的免疫反应。为了更好地了解Treg细胞介导的 在更具生理意义的环境中进行免疫调节，我们一直与动物保护计划密切合作， 加州大学圣地亚哥分校将建立一种新的协议来生成、维护和广泛表征稳定的 生理性微生物暴露的环境调节(PC)动物的储存库。通过服用这个 方法，两种成熟的小鼠模型，提供Treg细胞分离和Treg细胞特异性消融 将首先适应“肮脏”的条件。接下来，通过进行广泛的比较免疫 淋巴来源Treg细胞表型分析及单细胞测序研究 SPF小鼠和PC小鼠非淋巴组织中生理性微生物暴露对Treg细胞的影响 生物学将会被决定。最后，我们将检测PC小鼠Treg细胞的抑制功能 与其SPF相比，保持免疫动态平衡和控制持续的炎症 对口单位。我们的研究不仅将进一步扩展我们对Treg的基础知识 细胞依赖的免疫调节，但也提供了关键的见解的可能性和局限性 以Treg细胞为靶点治疗一系列人类免疫疾病。 。

Rigorous biocontainment prevents laboratory mice from being infected with natural pathogens and allows researchers to perform animal experiments in a reliable and reproducible manner. However, such specific pathogen-free (SPF) mice do not necessily model immune responses that occur in nature, and this may contribute to the often-reported disconnect between pre-clinical research and human clinical trials. Athough many key advances in biomedical research have been made possible by the study of SPF mice, there is now compelling evidence that microbial or viral experience can greatly impact immune pathophysiology. In past two decades, regulatory T (Treg) cells have emerged as a dedicated immune population crucial for the negative regulation of immune responses. Considering that Treg cell homeostasis and function can be greatly influenced by unique signals present in different tissue environments, it is conceiable that the microbial exposure outside the current laboratory setting could heavily impact Treg cells and their ability not only to establish immunological tolerance against ‘‘self’’ or innocuous foreign antigens, but also to keep in check effector immune responses to pathogens. To gain a better understanding of Treg cell-mediated immune regulation in a more physiological setting, we have worked closely with the Animal Care Program at UC San Diego to establish a new protocol to generate, maintain, and extensively characterize a stable repository of physiological microbe-exposed environmentally conditioned (PC) animals. By taking this approach, two well-establsihed mouse models that affords Treg cell isolation and Treg cell-specific ablation will be first adapted to the “dirty” condition. Next, through performing extensive comparative immune phenotype analysis and single-cell sequencing studies of Treg cells isolated from both lymphoid and non-lymphoid tissues in SPF mice and PC mice, the impact of physiological microbial exposure on Treg cell biology will be determined. Finally, we will examine the suppressor function of Treg cells from PC mice to maintain immune homeostasis and to control ongoing inflammation in comparison with their SPF counterparts. Together, our study will not only further extend our fundamental knowledge of Treg cell-dependent immune regulation but also provide critical insights into the possibilities and limitations of targeting Treg cells to treat a wide array of human immunological diseases. .