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: 10475627
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475627
• 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.

目前尚不清楚肠道细菌如何进行适应性免疫。共生体特异性T细胞很难 为了在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。这些包括管腔的隔离和免疫学上的无知，重定向 共系膜特异性T细胞进入Treg隔室，以及3型先天的负选择 淋巴样细胞(ILC3)。我们已经确定了一个共生-宿主交互的例子，其中 节段性丝状细菌(SFB)诱导抗原特异性的非炎症性Th17细胞反应。 因此，某些共生体确实会产生获得性免疫并产生效应性T细胞 显然是非炎性的。这一过程中涉及的机制尚不清楚，但有 非常感兴趣，因为它们可能有助于设计策略来抑制效应器T的炎症潜力 细胞，同时保留它们的效应器功能。我们还证明了这一过程是通过一种独特的 需要肠道巨噬细胞(MFS)的抗原提呈途径。在这里，我们建议调查 肠道MFS的机制作用以及诱导的Th17细胞的致病性。我们也 表明肠道上皮细胞参与了细菌和MFS之间的串扰，并将 研究这种相互作用的一种新的潜在机制。我们将调查以下具体目标： 1)我们将鉴定呈递SFB抗原的先天免疫亚群；2)我们将表征 肠上皮细胞、间质干细胞和树突状细胞在产生Th17细胞中的作用；3)我们将 研究产生的Th17细胞的致病性，并确定调节它们能力的基因 引起炎症；4)我们将检查是否有类似的抗原提呈途径参与 人类共生菌对Th17细胞的诱导作用。

项目成果

Intestinal epithelial cells as mediators of the commensal-host immune crosstalk.

• DOI: 10.1038/icb.2012.80
• 发表时间: 2013-03
• 期刊: IMMUNOLOGY AND CELL BIOLOGY
• 影响因子: 4
• 作者: Goto, Yoshiyuki;Ivanov, Ivaylo I.
• 通讯作者: Ivanov, Ivaylo I.

Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.

肠道微生物群特异性 Th17 细胞具有调节特性，并通过 c-MAF 和 IL-10 抑制效应 T 细胞。

• DOI: 10.1016/j.immuni.2023.11.003
• 发表时间: 2023
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Brockmann,Leonie;Tran,Alexander;Huang,Yiming;Edwards,Madeline;Ronda,Carlotta;Wang,HarrisH;Ivanov,IvayloI
• 通讯作者: Ivanov,IvayloI

Microbe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice.

• DOI: 10.1038/ncomms2718
• 发表时间: 2013
• 期刊: Nature communications
• 影响因子: 16.6

Induction of Th17 cells by segmented filamentous bacteria in the murine intestine.

• DOI: 10.1016/j.jim.2015.03.020
• 发表时间: 2015-06
• 期刊: Journal of immunological methods
• 影响因子: 2.2
• 作者: Farkas AM;Panea C;Goto Y;Nakato G;Galan-Diez M;Narushima S;Honda K;Ivanov II
• 通讯作者: Ivanov II

Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation.

• DOI: 10.1016/j.immuni.2014.03.005
• 发表时间: 2014-04-17
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Goto, Yoshiyuki;Panea, Casandra;Nakato, Gaku;Cebula, Anna;Lee, Carolyn;Diez, Marta Galan;Laufer, Terri M.;Ignatowicz, Leszek;Ivanov, Ivaylo I.
• 通讯作者: Ivanov, Ivaylo I.