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

项目摘要 栖息在胃肠道和其他哺乳动物粘膜中的肠道微生物群 表面。对宿主免疫的诱导、训练和功能发挥起着基础性作用 系统，但调节这些相互作用的确切机制尚未完全了解。 了解这些机制是设计新的治疗方法的关键一步。 纠正由生态失调和潜在的其他病症引起的免疫功能障碍的方法。 我们的初步研究表明，口服给药引起的肠道微生物群的改变 抗生素选择性破坏抗原特异性记忆CD 4 +T细胞的长期维持 在未经处理的小鼠中引发，并损害对感染的继发性反应。此外，我们还发现， 用抗生素治疗小鼠与细胞因子IL-1的表达减少有关， 15，这是维持记忆T细胞所必需的。这些结果共同引导我们 我假设，肠道微生物群通过以下方式调节记忆T细胞反应： 刺激促进细胞分化和/或维持的因子的表达， 抗原特异性记忆T细胞。在本申请中，我们将检验这一假设。具体 提出的目标是：1）确定肠道需求的机制 2）确定抗生素治疗是否改变记忆T细胞 人类受试者的反应。我们预计，这些研究将揭示 肠道微生物群和免疫系统之间相互作用的潜在机制 并可能为新的和改进的疫苗策略的设计提供信息

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