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

研究生理微生物暴露对调节性 T 细胞介导的免疫调节的影响

• 批准号: 10727298
• 负责人: Li-Fan Lu
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727298
• 关键词: Ablation; Animal Experimentation; Animal Experiments; Animals; Antigens; Autoimmunity; Biological Assay; Biomedical Research; Cell Separation; Cellular biology; Chronic Disease; Clinical Trials; Communities; Data; Dedications; Development; Disease; Environment; Exhibits; Exposure to; Fostering; Foundations; Functional disorder; Funding Opportunities; Future; Genetic; Germ-Free; Health; Heterogeneity; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunity; Immunological Models; Immunologics; Immunology; Immunophenotyping; In Vitro; Inbreeding; Infection; Infectious Agent; Inflammation; Knowledge; Laboratories; Laboratory Animals; Laboratory mice; Location; Lymphoid; Mediating; Microbe; Modeling; Mucosal Immune System; Mus; Nature; Pathologic; Phenotype; Physiological; Pilot Projects; Population; Protocols documentation; Recording of previous events; Regulatory T-Lymphocyte; Reliability of Results; Reporting; Reproducibility; Reproducibility of Results; Research; Research Personnel; Role; Science; Shapes; Signal Transduction; Solid; Suppressor-Effector T-Lymphocytes; T cell therapy; T-cell receptor repertoire; Tissues; Viral; Work; animal care; autoimmune inflammation; commensal microbes; comparative; dietary; experience; gain of function; germ free condition; immunoregulation; in vivo; insight; interest; loss of function; microbial; microbiome; mouse model; new therapeutic target; pathogen; pre-clinical research; preclinical study; prevent; programs; repository; single cell sequencing; transcriptome

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. .

严格的生物内在可防止实验室小鼠感染天然病原体，并允许 研究人员以可靠且可重复的方式进行动物实验。但是，这种具体 无病原体（SPF）小鼠不一定模拟自然界中发生的免疫反应，这可能 有助于临床前研究和人类临床试验之间经常报告的断开连接。 SPF小鼠的研究已经使生物医学研究的许多关键进展成为可能 现在，令人信服的证据表明微生物或病毒经验会极大地影响免疫生理学。在 在过去的二十年 免疫调查的负调节。考虑到Treg细胞稳态和功能可以是 受不同组织环境中存在的独特信号的极大影响，可以想象 当前实验室环境之外的微生物暴露可能会严重影响Treg细胞，并且其能力不影响 只是为了建立对“自我”或无害的外国抗原的免疫学宽容，但也要保持 检查对病原体的效应子免疫调查。为了更好地了解Treg细胞介导的 免疫调节在更加身体环境中，我们与动物护理计划紧密合作 加州大学圣地亚哥分校建立新的协议，以生成，维护和广泛表征稳定的 物理暴露于环境条件（PC）动物的存储库。通过这件事 方法，两个具有良好的小鼠模型，可提供Treg细胞隔离和Treg细胞特异性消融 将首先适应“肮脏”条件。接下来，通过执行广泛的比较免疫 从淋巴机和 SPF小鼠和PC小鼠的非淋巴组织，物理微生物暴露对Treg细胞的影响 生物学将被确定。最后，我们将检查来自PC小鼠的Treg细胞的抑制功能 与SPF相比，保持免疫稳态并控制正在进行的感染 同行。我们的研究不仅将进一步扩展我们对Treg的基本知识 依赖细胞的免疫调节，但也提供了对可能性和局限性的重要见解 靶向Treg细胞以治疗各种各样的人类免疫疾病。 。