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

项目摘要 肠道中居住着一种复杂的共生细菌群落，称为微生物区系， 它们在塑造宿主生理和免疫功能方面起着基础性作用。一般说来，T细胞保留 对共生细菌抗原一无所知，或者如果被激活就会采取调控的命运。然而，一小部分人 共生细菌抗原已被鉴定为可激发效应性T细胞反应。这种共生关系- 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，共生反应性T细胞也被证明影响免疫系统对 其他情况下，例如在自身免疫性疾病和癌症期间。 这一应用重点是共生细菌物种阿克曼西亚粘液嗜粘菌，它定植于 无论是健康的老鼠还是人类。肠道中出现的粘液嗜酸杆菌与变化有关。 在宿主免疫功能和对一些疾病状态的保护方面，尽管机制 这些影响的潜在原因尚不清楚。巴顿实验室已经开发出强大的工具来追踪T细胞 对粘液假单胞菌的反应。他们最近使用这些工具证明了粘液弧菌诱导了一种独特的 与其他共生物种不同的是，依赖于上下文的T细胞反应。在……里面 具有最小微生物区系的灵知生态型小鼠，粘液嗜酸杆菌能引起明确的T滤泡辅助细胞反应； 然而，在SPF微生物区系更复杂的小鼠中，这种细菌通过多个 效应器表型。这些结果表明，对粘液嗜酸杆菌的免疫反应是不同的，并且 取决于细菌的存在或不存在以外的线索。 我们的目标是了解粘液弧菌诱导特定类型T细胞的机制 反应，以及改变抗共生免疫反应对宿主健康的影响。在AIM 1，我们将在几种定义的微生物的背景下检测对粘液嗜酸杆菌的免疫应答。 群落，以研究其他共生物种如何改变粘液嗜酸杆菌特异性T细胞 回应。在目标2中，我们将表征负责呈递粘液嗜酸杆菌抗原的APC。 T细胞对粘液嗜酸杆菌的反应是多种多样的。最后，在目标3中，我们将研究如何 粘液金黄色葡萄球菌特异性T细胞反应性质的改变影响宿主健康。总而言之，这些研究 将提供对免疫系统如何响应微生物区系以及如何免疫的机械性洞察 对共生细菌的反应会改变宿主的生理。

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.