Differential Regulation of T Cell Responses to the Commensal Bacterium Akkermansia Muciniphila

T 细胞对共生细菌 Akkermansia Muciniphila 反应的差异调节

• 批准号: 10618143
• 负责人: Shaina L Carroll
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618143
• 关键词: Adaptive Immune System; Adopted; Affect; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Bacteria; Bacterial Antigens; CD4 Positive T Lymphocytes; Cell Communication; Cells; Colitis; Communities; Complex; Cues; Development; Disease; Education; Gnotobiotic; Goals; Gram-Negative Bacteria; Health; Helicobacter hepaticus; Helper-Inducer T-Lymphocyte; Home; Homeostasis; Human; Immune; Immune response; Immune system; Immunologic Receptors; Immunologist; In Vitro; Infection; Intestines; Knowledge; Label; Learning; Link; Malignant Neoplasms; Metabolism; Methods; Mucins; Mus; Nature; Patients; Phenotype; Physiological Processes; Physiology; Play; Process; Proteins; Role; Sampling; Severity of illness; Shapes; Signal Transduction; Systems Development; T cell regulation; T cell response; T-Lymphocyte; Testing; Therapeutic; bacterial community; cancer therapy; commensal bacteria; cytokine; effector T cell; enteric pathogen; gut inflammation; host colonization; immune function; immune system function; insight; member; microbial community; microbiota; pathogenic bacteria; response; single-cell RNA sequencing; tool

Project Summary The intestines are inhabited by a complex community of commensal bacteria known as the microbiota, which play a fundamental role in shaping host physiology and immune function. In general, T cells remain ignorant of commensal bacterial antigens, or adopt a regulatory fate if activated. However, a small number of commensal bacterial antigens have been identified that elicit effector T cell responses. Such commensal- reactive T cells can alter how the immune system responds to local challenges, such as intestinal pathogens. Notably, commensal-reactive T cells have also been shown to influence how the immune system responds in other contexts, such as during autoimmune disease and cancer. This application focuses on the commensal bacterial species Akkermansia muciniphila, which colonizes both healthy mice and humans. The presence of A. muciniphila in the intestines has been linked with changes in host immune function, and protection against a number of disease states, although the mechanisms underlying these effects are unclear. The Barton lab has developed powerful tools for tracking the T cell response to A. muciniphila. They recently used these tools to demonstrate that A. muciniphila induces a unique context-dependent T cell response unlike what has been described for other commensal species. In gnotobiotic mice with a minimal microbiota, A. muciniphila elicits a defined T follicular helper cell response; however, in mice with a more complex SPF microbiota, this bacterium elicits helper T cells with multiple effector phenotypes. These results suggest that the immune response to A. muciniphila is variable and depends on cues other than the presence or absence of the bacteria. Our goal is to understand the mechanisms by which A. muciniphila induces specific types of T cell responses, as well as the implications for host health of altering the anti-commensal immune response. In Aim 1, we will examine the immune response to A. muciniphila in the setting of several defined microbial communities in order to examine how additional commensal species alter the A. muciniphila-specific T cell response. In Aim 2, we will characterize the APCs responsible for presenting A. muciniphila antigens in contexts in which the T cell response to A. muciniphila is varied. Finally, in Aim 3, we will examine how changes in the nature of the A. muciniphila-specific T cell response impact host health. Together, these studies will provide mechanistic insight into how the immune system responds to the microbiota and how immune responses to commensal bacteria can alter host physiology.

项目摘要 肠道内有一个复杂的肠道细菌群落，称为微生物群， 其在形成宿主生理学和免疫功能中起基本作用。总的来说，T细胞 不知道肠道细菌抗原，或者如果被激活则采取调节命运。但少数 已经鉴定了引起效应T细胞应答的肠道细菌抗原。这样的讽刺- 反应性T细胞可以改变免疫系统对局部挑战（如肠道病原体）的反应。 值得注意的是，淋巴细胞反应性T细胞也被证明会影响免疫系统在免疫应答中的反应。 其他情况，例如自身免疫性疾病和癌症期间。 本申请集中于嗜粘蛋白阿克曼氏菌（Akkermansia muciniphila）， 包括健康的老鼠和人类。A.肠道中的嗜粘蛋白菌与 在宿主的免疫功能，并保护对一些疾病的状态，虽然机制 这些影响的根本原因尚不清楚。巴顿实验室已经开发出强大的工具来跟踪T细胞 回答A。嗜粘蛋白菌。他们最近用这些工具证明了A.嗜粘蛋白诱导了一种独特的 背景依赖性T细胞应答，与其他哺乳动物物种所描述的不同。在 具有最小微生物群的无菌小鼠，A.嗜粘蛋白菌定义的T滤泡辅助细胞反应; 然而，在具有更复杂的SPF微生物群的小鼠中，这种细菌刺激具有多种 效应子表型这些结果表明，A.嗜粘蛋白菌是可变的， 取决于细菌存在与否以外的线索。 我们的目标是了解A.嗜粘蛋白菌诱导特定类型的T细胞 反应，以及宿主健康的影响，改变抗肿瘤免疫反应。在Aim中 1，我们将检查对A的免疫反应。在几种确定的微生物环境中的嗜粘蛋白 群落，以研究如何额外的植物物种改变A。嗜粘蛋白特异性T细胞 反应在目标2中，我们将描述负责呈递A.嗜粘蛋白抗原 在这种情况下，T细胞对A.嗜粘蛋白菌是多种多样的。最后，在目标3中，我们将研究如何 A.性质的变化嗜粘蛋白特异性T细胞应答影响宿主健康。这些研究一起 将提供关于免疫系统如何对微生物群做出反应以及免疫系统如何对微生物群做出反应的机制性见解。 对寄生细菌的反应可以改变宿主的生理机能。