Microbiome and immunosenescence of T cells repertoire

微生物组和 T 细胞库的免疫衰老

• 批准号: 10259681
• 负责人: LESZEK IGNATOWICZ
• 金额: $ 38.98万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259681
• 关键词: Age; Aging; Anti-Inflammatory Agents; Antigens; Bacteria; CD4 Positive T Lymphocytes; Cells; Chronic; Collection; Data; Disease; Ecosystem; Elderly; Epitopes; Equilibrium; FOXP3 gene; Functional disorder; Genome; Germ-Free; Goals; Grant; Health Benefit; Homeostasis; Human; Immune; Immune system; Immunity; Immunization; Individual; Inflammation; Interleukin-10; Intestines; Lead; Longevity; Mediating; Metabolism; Microbe; Mucous Membrane; Mus; Oligonucleotides; Patients; Peptides; Play; Probiotics; Regulatory T-Lymphocyte; Research; Role; Specificity; Standardization; System; T-Lymphocyte; TNFRSF11B gene; Testing; Therapeutic; Transplantation; Work; age related; base; commensal microbes; cytokine; design; dysbiosis; enteric pathogen; gut microbiota; immunoregulation; immunosenescence; improved; inflammatory disease of the intestine; intestinal homeostasis; microbial; microbiome; microbiota; microorganism antigen; novel therapeutic intervention; pathogen exposure; prevent; response; therapy design; tissue injury; transcription factor

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.

肠道微生物群是肠道CD 4 T细胞识别抗原的主要贡献者 细胞这些抗原如何影响CD 4 T细胞免疫衰老及其效应功能 在老年小鼠和人类中的作用尚不清楚。因此，需要制定标准化的 微生物植物群，其具有可管理的大小，并且类似于当 施用于年老体弱的个体将重新平衡他们的肠道内稳态。这个目标 建议是测试这种新的寡克隆小鼠肠上皮细胞集合（寡-MM）， 通过系统和基于基因组的方法来概括完整的微生物组， 帮助恢复老化的免疫系统。特别是，我们将研究寡MM微生物群如何 其主要成分Akkermasia municiphila与Cd 4 T细胞相互作用， 这些细胞从细菌中识别的抗原决定簇。在目标1中，我们将研究如何具体 肠梗阻对老年小鼠CD 4 T细胞活化和库影响在我们的目标2 我们将证明A. municiphila衍生抗原诱导幼稚CD 4Foxp 3- T细胞 转化为CD 4Foxp 3 + pT细胞，并显著增加老年小鼠中这些细胞的数量。 我们假设A. municiphila可以改善老年小鼠 耐受肠道微生物群和减少免疫衰老。总的来说，这项研究将有助于 制定基于严格控制的微生物群疗法的新策略， 老年人的炎症