Microbiome and immunosenescence of T cells repertoire

肠道微生物区系是肠道CD4T识别抗原的主要贡献者 细胞。这些抗原如何影响CD4T细胞免疫衰老及其效应器功能 在老年老鼠和人类身上的作用尚不清楚。因此，有必要制定一种标准化的 微生物区系，具有可管理的大小，类似于自然微生物群，当 给年老体弱的人服用该药将重新平衡他们的肠道内环境平衡。这样做的目的是 建议测试这种新的小鼠肠道连结的寡克隆集合(Olio-MM)， 由系统和基于基因组的方法设计来概括完整的微生物组可以 帮助恢复老化的免疫系统。特别是，我们将调查Olio-MM微生物群如何 其主要成分Akkermasia municiPhila与CD4T细胞相互作用，发现免疫 这些细胞从这种细菌中识别的表位。在目标1中，我们将调查具体到 肠道共生影响老年小鼠CD4T细胞的活化和谱系。在我们的目标2 我们将证明，市政支原体来源的抗原可以诱导幼稚的CD4Foxp3-T细胞 转化为CD4Foxp3+pTregs，并显著增加老年小鼠中这些细胞的数量。 我们假设，对老龄小鼠的治疗性给药可以改善 对肠道微生物区系的耐受性和降低免疫衰老。总体而言，这项研究将有所帮助 开发基于严格控制的微生物群疗法的新策略来控制肠道 老年人的炎症。

The intestinal microbiota is a major contributor of antigens recognized by intestinal CD4 T cells. How these antigens influence CD4 T cells immunosenescence and their effector functions in old mice and humans remains unclear. Therefore, there is a need to develop a standardized microbial flora that has a manageable size and resembles natural microbiome that when administered to old, frail individuals will rebalance their intestinal homeostasis. The goal of this proposal is to test if this new oligoclonal collection of mouse intestinal commensals (oligo-MM), designed by system and genome-based approaches to recapitulate complete microbiome can help revitalize an aging immune system. In particular, we will investigate how oligo-MM microbiota and its main component Akkermasia municiphila interacts with Cd4 T cells and discover immune epitopes that these cells recognize from this bacteria. In Aim 1 we will investigate how specific intestinal commensals influence activation and repertoire of CD4 T cells in old mice. In our Aim 2 we will demonstrate that A. municiphila derived antigens induce naïve CD4Foxp3- T cells conversion to CD4Foxp3+ pTregs and substantially increase the number of these cells in old mice. We hypothesize that the therapeutic administration of A. municiphila to old mice can improve tolerance to intestinal microbiota and reduce immunosenescence. Overall this research will help develop new strategies based on strictly controlled microbiota-based therapies to control intestinal inflammation in elderly.