Mechanisms of Mucosal Th17 Cell Induction By Segmented Filamentous Bacteria

分节丝状细菌诱导粘膜 Th17 细胞的机制

• 批准号: 10223273
• 负责人: Ivaylo Ivanov Ivanov
• 金额: $ 58.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223273
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Automobile Driving; Award; Bacteria; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; Dendritic Cells; Development; Environment; Epithelial Cells; Funding; Generations; Genes; Genetic Models; Homeostasis; Human; Immune; Immune response; Immunologics; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Lamina Propria; Lymphoid Cell; Microbe; Mucous Membrane; Mus; Nature; Pathogenicity; Pathway interactions; Peyer' s Patches; Phagocytosis; Process; Regulatory T-Lymphocyte; Reporting; Research Design; Role; T cell response; T-Lymphocyte; Testing; Tissues; adaptive immunity; cellular targeting; commensal bacteria; design; effector T cell; gut bacteria; gut microbiota; interest; intestinal epithelium; macrophage; mesenteric lymph node; mucosal microbiota; novel; pathogen; pathogenic bacteria; preservation; prevent; resident commensals; response

How resident gut bacteria engage adaptive immunity is not clear. Commensal specific T cells are difficult to detect in the LP and multiple mechanisms have been described that prevent development of such cells at steady state. These include sequestration in the lumen and immunological ignorance, re-direction of commensal-specific T cells into the Treg compartment, and negative selection by type 3 innate lymphoide cells (ILC3). We have identified an example of commensal-host interaction in which segmented filamentous bacteria (SFB) induce an antigen-specific non-inflammatory Th17 cell response. Therefore, certain commensals do engage adaptive immunity and generate effector T cells that are apparently non-inflammatory. The mechanisms involved in this process are not known, but are of significant interest, because they may help design strategies to curb inflammatory potential of effector T cells, while preserving their effector function. We also showed that this process occurs through a unique antigen-presentation pathway that requires intestinal macrophages (Mfs). Here we propose to investigate the mechanistic role of intestinal Mfs as well as the pathogenicity of the induced Th17 cells. We also show that intestinal epithelial cells are involved in the crosstalk between the bacteria and Mfs, and will investigate a novel potential mechanism of this interaction. We will investigate the following specific aims: 1) we will identify the innate immune subset presenting SFB antigens; 2) we will characterize the co- operative role of intestinal epithelial cells, Mfs and dendritic cells in generating Th17 cells; 3) we will investigate the pathogenicity of the generated Th17 cells and identify genes that regulate their ability to cause inflammation; 4) we will examine whether a similar antigen-presentation pathway is involved in induction of Th17 cells by human commensal bacteria.

肠道细菌如何参与适应性免疫尚不清楚。共生特异性T细胞很难 在LP中检测，并且已经描述了防止这种发展的多种机制。 细胞处于稳定状态。这些措施包括在管腔隔离和免疫无知，重定向 的肿瘤特异性T细胞进入Treg区室，并通过3型先天性 淋巴样细胞（ILC 3）。我们已经确定了一个植物-宿主相互作用的例子， 分节丝状细菌（SFB）诱导抗原特异性非炎性Th 17细胞应答。 因此，某些细胞确实参与了适应性免疫，并产生了效应T细胞， 显然没有炎症这一过程中涉及的机制尚不清楚，但 重要的兴趣，因为它们可能有助于设计策略来抑制效应T细胞的炎症潜力， 细胞，同时保留其效应器功能。我们还发现，这一过程是通过一种独特的 需要肠巨噬细胞（Mfs）的抗原呈递途径。在这里，我们建议调查 肠道Mfs的机制作用以及诱导的Th 17细胞的致病性。我们也 表明肠上皮细胞参与细菌和Mfs之间的串扰， 研究这种相互作用的一种新的潜在机制。我们将研究以下具体目标： 1)我们将鉴定呈递SFB抗原的先天免疫亚群; 2）我们将表征共- 肠上皮细胞、Mfs和树突状细胞在产生Th 17细胞中的作用; 3）我们将 研究产生的Th 17细胞的致病性，并鉴定调节其致病能力的基因。 引起炎症; 4）我们将检查是否有类似的抗原呈递途径参与炎症反应。 通过人大肠杆菌诱导Th 17细胞。