Exploring the function of a novel, microbiota-regulated gene in T cells

描述（由申请人提供）：寄主-共生体相互作用的研究是一个快速发展的领域。最近的研究进展揭示了共生菌在塑造宿主免疫系统、代谢和预防自身免疫方面的作用。因此，微生物群已成为操纵人类健康的新机制。尽管在过去几年中已经收集了大量的知识，但我们对微生物群影响这些不同宿主途径的分子机制的理解仍存在差距。T淋巴细胞是控制适应性免疫反应的关键细胞类型之一，导致抗原特异性免疫和免疫记忆。在肠道和全身部位，微生物群控制着多种T细胞亚型的发育，包括炎症和调节性T细胞。虽然很多研究都在了解肠道T细胞生物学，但很少有人关注微生物群如何影响全身T细胞功能。鉴于共生生物自真核生物诞生以来就已经存在，很可能宿主体内已经进化出一种复杂的分子机制来平衡与肠道外微生物群和免疫系统的关系。只有当我们分析免疫系统在没有微生物群的情况下是如何发育的，我们才能了解其中的大部分机制。在完全无菌环境中出生和饲养的动物（无菌小鼠）是一个强大的比较工具，可以开始发现宿主体内控制共生相互作用的新途径。利用这种方法，我们发现了T淋巴细胞内一个由微生物群动态调节的新基因。尽管ERDR1基因在关键的免疫细胞中有很高的表达水平，但到目前为止，它还没有被注意到。我们提出的初步数据表明，ERDR1在T细胞生物学和宿主健康中是一个重要的功能相关基因。这项资助旨在更好地了解ERDR1影响宿主健康和微生物群落结构的机制。

DESCRIPTION (provided by applicant): The study of commensal-host interactions is a rapidly growing field. Recent advances have uncovered roles for commensal bacteria in shaping the host immune system, metabolism, and pre-disposition or protection from autoimmunity. Thus, the microbiota has emerged as novel mechanism to manipulate human health. Despite the plethora of knowledge that has been gleaned over the last several years, there is gap in our understanding of the molecular mechanisms by which the microbiota can influence these diverse host pathways. T lymphocytes are one of the key cell types that govern adaptive immune responses that lead to antigen specific immunity and immunological memory. In both the intestine and systemic body sites, the microbiota governs the development of multiple T cell subtypes including inflammatory and regulatory T cells. While much research has gone into understanding intestinal T cell biology, little focus has been placed on how the microbiota can influence systemic T cell function. Given that commensal organisms have been presence since the birth of eukaryotic life, it is likely that a sophisticated molecular machinery has evolved witin the host to balance the relationship with the microbiota and the immune system outside of the gut. Much of this machinery will only be realized if we analyze how the immune system develops in the absence of the microbiota. Animals that are born and reared in a completely sterile environment (germfree mice) are a powerful, comparative tool to begin the discovery of novel pathways within the host that govern commensal interactions. Using this approach, we have uncovered a novel gene within T lymphocytes that is dynamically regulated by the microbiota. This gene, ERDR1, has gone un- noticed to this point despite its very high level of expression with key immune cells. We present preliminary data within this proposal that demonstrates that ERDR1 is an important functionally relevant gene in T cell biology and host health. This grant proposes to better understand the mechanisms by which ERDR1 influences host health and microbial community structure.