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.

居民肠道细菌如何使自适应免疫尚不清楚。共生特异性T细胞困难 已经描述了在LP中检测到的多种机制，以防止这种发展 细胞处于稳定状态。其中包括腔体中的隔离和免疫学的无知，重新指导 分别特异性的T细胞进入Treg室，而按3型先天性选择负选择 淋巴细胞（ILC3）。我们已经确定了一个共同主持人相互作用的示例 分段的丝状细菌（SFB）诱导抗原特异性的非炎性TH17细胞反应。 因此，某些共生确实具有适应性免疫，并产生效应T细胞 显然是非炎症的。此过程中涉及的机制尚不清楚，但 引起了重大兴趣，因为它们可能有助于设计策略来遏制效应的炎症潜力 细胞，同时保留其效应子功能。我们还表明，这个过程是通过独特的 需要肠道巨噬细胞（MFS）的抗原呈递途径。在这里我们建议调查 肠道MFS的机械作用以及诱导的Th17细胞的致病性。我们也是 表明肠上皮细胞与细菌和MF之间的串扰有关，并将 研究这种相互作用的新型潜在机制。我们将调查以下具体目标： 1）我们将确定呈现SFB抗原的先天免疫子群； 2）我们将表征共同 肠上皮细胞，MFS和树突状细胞在产生Th17细胞中的手术作用； 3）我们会的 研究生成的Th17细胞的致病性，并确定调节其能力的基因 引起炎症； 4）我们将检查是否涉及类似的抗原呈递途径 人类共生细菌诱导Th17细胞。

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.

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

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

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.