Maintenance of mucosal homeostasis by commensal Th17 cells

共生 Th17 细胞维持粘膜稳态

• 批准号: 10462753
• 负责人: Ivaylo Ivanov Ivanov
• 金额: $ 56.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462753
• 关键词: Address; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Automobile Driving; Bacteria; CD4 Positive T Lymphocytes; Carrier Proteins; Cell physiology; Cells; Complex; Data; Development; Disease; Endocytosis; Epithelial; Epithelial Cells; Exocytosis; Fostering; Generations; Health; Homeostasis; Human; Immune; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Interleukin-10; Intestines; Investigation; Maintenance; Microbe; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nature; Pathway interactions; Peptides; Phenotype; Play; Process; Reaction; Regulation; Role; Sampling; Side; Sterility; Symbiosis; T cell response; T-Lymphocyte; Testing; Tissues; antigen processing; base; commensal microbes; cytokine; experimental study; factor C; gut inflammation; immunoreaction; in vivo; insight; intestinal epithelium; intestinal homeostasis; microbial; mucosal site; mucosal vaccine; novel; pathogen; prevent; programs; receptor; response; sensor; transcription factor; transcytosis

Mucosa are sites of conventional immune system attack for defense against invasive pathogens. Mucosa were also once regarded simply as inert barriers preventing commensal microbes from accessing sterile tissues. Instead, emerging evidence suggests a complex interplay between commensal microbes, barrier epithelial cells, and the immune system that is essential for local and systemic homeostasis of the host. We have recently provided insight into how recognition of commensal components by epithelial and innate immune cells triggers a specific immune reaction and why the nature of this reaction could foster host- microbe symbiosis instead of outright microbial rejection. Specifically, we showed that antigen acquisition be intestinal epithelial cells (IECs) of commensal antigens drives a non-pathogenic commensal Th17 cell response. Here we propose to mechanistically examine the fate of intracellular IEC antigens and the role of IECs in the process, as well as the phenotype and function of the generated Th17 cells. We will address these mechanism by pursuing two specific aims to explore 1) Role of IECs in priming of commensal T cell responses and 2) Generation and function of anti-inflammatory commensal Th17 cells. Our studies address fundamental mechanisms of mucosal immunity to commensal microbes and if successful will provide novel mechanisms of IEC function, as well as pathways for generation of protective mucosal T cell responses.

粘膜是常规免疫系统防御侵袭性病原体的场所。粘膜 也曾被认为是阻止共生微生物获得不育的惰性屏障 纸巾。相反，新出现的证据表明，共生微生物之间存在复杂的相互作用， 上皮细胞，以及对宿主的局部和全身动态平衡至关重要的免疫系统。 我们最近提供了关于上皮和先天如何识别共生成分的洞察力 免疫细胞触发一种特定的免疫反应，以及为什么这种反应的性质可以培养宿主- 微生物共生，而不是彻底的微生物排斥。具体地说，我们证明了抗原的获得 共生抗原的BE肠上皮细胞(IECS)驱动非致病性共生Th17细胞 回应。在这里，我们建议从机械上研究细胞内IEC抗原的命运及其作用 IECS在这一过程中的作用，以及产生的Th17细胞的表型和功能。我们将解决 这些机制通过追求两个特定的目的来探索：1)IECS在共生T细胞启动中的作用 2)抗炎共生Th17细胞的产生和功能。我们的研究 解决对共生微生物的粘膜免疫的基本机制，如果成功，将 提供IEC功能的新机制以及产生保护性粘膜T细胞的途径 回应。