Investigating the requirement of the commensal microbiota for long term T cell immunity

研究共生微生物群对长期 T 细胞免疫的需求

• 批准号: 10132236
• 负责人: Gislaine A Martins
• 金额: $ 25.05万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-24 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132236
• 关键词: 16S ribosomal RNA sequencing; Adoptive Transfer; Antibiotic Therapy; Antibiotics; Antigens; Area; Bacteria; Cell physiology; Cells; Complex; Confocal Microscopy; Development; Epithelial; Experimental Models; Flow Cytometry; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; Germ-Free; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Impairment; Individual; Infection; Interleukin-15; Intestines; Light; Lung; Lymphoid Tissue; Maintenance; Memory; Mucous Membrane; Mus; Oral Administration; Physiology; Play; Predisposition; Reporter; Role; Sampling; Shapes; Signal Transduction; Source; Stains; Surface; System; Systems Development; T cell response; T memory cell; T-Lymphocyte; Testing; Training; Vaccination; Vaccines; Yellow Fever Vaccine; cell type; cohort; commensal microbes; cytokine; design; dysbiosis; energy balance; experimental study; fungus; germ free condition; gut microbiota; human subject; immune system function; immunoregulation; improved; in vivo; influenza infection; memory CD4 T lymphocyte; microbiota; microorganism; mouse model; novel therapeutic intervention; novel vaccines; peripheral blood; reconstitution; response; transcriptome sequencing

PROJECT SUMMARY The commensal microbiota inhabiting the gastrointestinal tract and other mammalian mucosal surfaces. plays fundamental roles on the induction, training and function of the host immune system, but the exact mechanisms that regulate these interactions are not fully understood. Understanding these mechanisms is a crucial step towards designing new therapeutic approaches to correct immune dysfunction caused by dysbiosis and potentially other conditions. Our initial studies show that alterations of the intestinal microbiota induced by oral administration of antibiotics selectively disrupt long-term maintenance of antigen-specific memory CD4+T cells primed in untreated mice, and impairs secondary responses to infection. In addition, we found that treatment of mice with antibiotics is associated with reduced expression of the cytokine IL- 15, which is required for maintenance of memory T cells. Together, these results led us to hypothesize that the commensall microbiota regulates memory T cell responses by stimulating the expression of factors that promotes differentiation and/ or maintenance of antigen-specific memory T cells. In this application, we will test this hypothesis. The specific aims proposed are 1) Identify mechanisms underlying the requirement of the intestinal microbiota for T cell memory and 2) Determine if antibiotic treatment alters memory T cell responses in human subjects. We anticipate that these studies will shed light on the mechanisms underlying the crosstalk between the commensal microbiota and the immune system and may inform the design of new and improved vaccine strategies

项目概要 栖息在胃肠道和其他哺乳动物粘膜的共生微生物群 表面。对宿主免疫的诱导、训练和功能发挥重要作用 系统，但调节这些相互作用的确切机制尚不完全清楚。 了解这些机制是设计新疗法的关键一步 纠正由生态失调和其他潜在情况引起的免疫功能障碍的方法。 我们的初步研究表明，口服给药可引起肠道微生物群的改变 抗生素选择性破坏抗原特异性记忆 CD4+T 细胞的长期维持 在未经治疗的小鼠中引发，并损害对感染的继发反应。此外，我们还发现 用抗生素治疗小鼠与细胞因子 IL- 表达减少有关 15，这是维持记忆T细胞所必需的。这些结果共同引导我们 假设共生微生物群通过以下方式调节记忆 T 细胞反应 刺激促进分化和/或维持的因子的表达 抗原特异性记忆T细胞。在此应用中，我们将测试这个假设。具体的 提出的目标是 1) 确定肠道需求的潜在机制 T 细胞记忆的微生物群以及 2) 确定抗生素治疗是否会改变记忆 T 细胞 人类受试者的反应。我们预计这些研究将揭示 共生微生物群与免疫系统之间串扰的机制 并可能为新的和改进的疫苗策略的设计提供信息