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 肠子被一个复杂的共生细菌居住，称为菌群， 在塑造宿主生理和免疫功能方面起着基本作用。通常，T细胞保留 对共生细菌抗原一无所知，或者如果被激活，则采用调节命运。但是，少数 已经鉴定出共生细菌抗原引起效应T细胞反应。这样的共鸣 - 反应性T细胞可以改变免疫系统对局部挑战的反应，例如肠道病原体。 值得注意的是，也已证明共生反应性T细胞会影响免疫系统在 其他情况，例如在自身免疫性疾病和癌症期间。 该应用集中于共生细菌种类akkermansia粘膜，该物种在殖民地上定居 健康的老鼠和人类。肠中粘曲霉的存在与变化有关 在宿主免疫功能和对许多疾病状态的保护 这些影响的基础尚不清楚。 Barton Lab开发了用于跟踪T细胞的强大工具 对A.粘曲霉的反应。他们最近使用这些工具证明了粘拟霉菌会引起独特的 与其他共生物种所描述的内容不同，依赖上下文依赖性的T细胞反应。在 gnotobiotic小鼠具有最小的微生物群，粘拟杆菌会引起定义的T卵泡辅助细胞反应； 但是，在具有更复杂的SPF菌群的小鼠中，该细菌会引起辅助辅助T细胞 效应子表型。这些结果表明，对粘曲霉的免疫反应是可变的，并且 取决于提示，而不是细菌的存在或不存在。 我们的目标是了解A. muciniphila诱导特定类型的T细胞的机制 反应，以及对改变抗常见免疫反应的宿主健康的影响。目标 1，我们将在几个定义的微生物的情况下检查对粘曲霉的免疫反应 社区为了研究其他共生物种如何改变粘膜曲霉特异性T细胞 回复。在AIM 2中，我们将表征负责在 T细胞对粘曲霉的T细胞响应的上下文各不相同。最后，在AIM 3中，我们将研究如何 粘曲霉​​特异性T细胞反应影响宿主健康的性质变化。在一起，这些研究 将提供有关免疫系统如何对微生物群反应以及免疫的反应的机械洞察力 对共生细菌的反应可以改变宿主生理。