Dendritic Cell Control of Intestinal T Cell Responses

树突状细胞控制肠道 T 细胞反应

• 批准号: 8868105
• 负责人: Adam Lacy-Hulbert
• 金额: $ 37.19万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868105
• 关键词: Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmunity; Biochemical; CD4 Positive T Lymphocytes; Cell Communication; Cell Differentiation process; Cells; Cellular biology; Chronic; Colitis; Complex; Data; Dendritic Cells; Dendritic cell activation; Development; Diet; Disease; Equilibrium; Generations; Goals; Helper-Inducer T-Lymphocyte; Human; IL17 gene; Immune Tolerance; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integrins; Interferon Type II; Intestines; Knockout Mice; Licensing; Link; Maintenance; Mediating; Molecular; Mus; Myeloid Cells; Pathology; Peptide Hydrolases; Phenotype; Play; Population; Prevention; Primary Cell Cultures; Process; Production; Property; Publishing; Reaction; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Surface; T cell response; T-Lymphocyte; Testing; Th1 Cells; Transforming Growth Factor beta; Translating; Work; base; commensal microbes; cytokine; in vivo; innovation; interleukin-23; intestinal epithelium; microorganism; mucosal site; pathogen; prevent; response

DESCRIPTION (provided by applicant): Mucosal surfaces such as the intestinal epithelium provide a complex challenge to the immune system, as they must maintain effective immunity against potential pathogen attack while also tolerating commensal microorganisms and dietary antigens. The balance between tolerance and immunity is mediated in large part by the specialized T cell populations, regulatory T cells (Tregs) and Th17 cells. Disruption of the balance between these subsets has been heavily implicated in causing colitis through studies in both mice and humans. Furthermore, Th17 cells are emerging as contributors to many other inflammatory and autoimmune disorders. Understanding how Th17 responses are initiated and regulated is therefore critical to our understanding of both intestinal immunity and chronic inflammatory disease. Our long term goal is to understand how Dendritic Cells (DCs) and other antigen presenting cells initiate and maintain the correct balance of T-helper cell subsets. The objective in this application is to establish how DCs regulate T cell responses to TGF-ß and control Th17 cell differentiation. The rationale for this work is that understanding this process has the potential to translate into new therapies for Th17-mediated diseases. Our central hypothesis is that DC expression of αvß8 and subsequent activation of TGF-ß controls induction and maintenance of Th17 responses. Based on published work and preliminary data, this hypothesis will be tested in three specific aims: (1) Determine how αv integrins expressed by DCs regulate Th17 cell differentiation, particularly the generation of IL17/ IFN-γ-expressing cells associated with autoimmunity. Conditional knockout mice will be used to study the role for αv integrins in vivo, and results will be extended to humans though primary cell culture. (2) Understand how ß8 expression is regulated in DCs during homeostatic regulation and following infection. (3) Determine the mechanisms by which αvß8 function is regulated on DCs using cell biology and biochemical approaches. This approach is innovative as it focuses on the role of DCs in 'licensing' T cell responses to TGF-ß. The proposed work is significant because it will provide a much needed understanding of how DCs promote the initiation of Th17 cells in the intestine and regulate their subsequent differentiation in response to environmental and infectious challenges.

描述（由申请人提供）：诸如肠上皮之类的粘膜表面对免疫系统提出了复杂的挑战，因为它们必须保持针对潜在病原体攻击的有效免疫力，同时还耐受共生微生物和饮食抗原。耐受性和免疫性之间的平衡是介导的。很大程度上是由专门的 T 细胞群、调节性 T 细胞 (Treg) 和 Th17 细胞引起的，通过研究发现，这些亚群之间的平衡破坏与结肠炎的引起密切相关。此外，Th17 细胞正在成为许多其他炎症和自身免疫性疾病的贡献者，因此了解 Th17 反应的启动和调节对于我们了解肠道免疫和慢性炎症疾病至关重要。了解树突状细胞 (DC) 和其他抗原呈递细胞如何启动和维持 T 辅助细胞亚群的正确平衡 本应用的目标是确定 DC 如何调节 T 细胞对 TGF-ß 的反应并控制 Th17 细胞。这项工作的基本原理是，了解这一过程有可能转化为 Th17 介导的疾病的新疗法。我们的中心假设是 αvß8 的 DC 表达和随后的 TGF-ß 激活控制 Th17 反应的诱导和维持。根据已发表的工作和初步数据，该假设将在三个具体目标上进行检验：（1）确定 DC 表达的 αv 整合素如何调节 Th17 细胞分化，特别是表达 IL17/IFN-γ 的生成细胞 条件性敲除小鼠将用于研究 αv 整合素在体内的作用，结果将通过原代细胞培养扩展到人类 (2) 了解 ß8 表达在稳态调节和感染后如何受到调节。 (3) 使用细胞生物学和生化方法确定 DC 上 αvß8 功能的调节机制。这种方法具有创新性，因为它重点关注 DC 在“许可”T 细胞中的作用。回应 TGF-ß.拟议的工作意义重大，因为它将提供人们急需的了解 DC 如何促进肠道中 Th17 细胞的启动并调节其随后的分化以应对环境和感染挑战。

项目成果

Integrin αv in the mechanical response of osteoblast lineage cells.

• DOI: 10.1016/j.bbrc.2014.04.006
• 发表时间: 2014-05-02
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Kaneko, Keiko;Ito, Masako;Naoe, Yoshinori;Lacy-Hulbert, Adam;Ikeda, Kyoji
• 通讯作者: Ikeda, Kyoji

αv Integrins regulate germinal center B cell responses through noncanonical autophagy.

αv 整合素通过非典型自噬调节生发中心 B 细胞反应。

• DOI: 10.1172/jci99597
• 发表时间: 2018
• 期刊: The Journal of clinical investigation
• 作者: Raso,Fiona;Sagadiev,Sara;Du,Samuel;Gage,Emily;Arkatkar,Tanvi;Metzler,Genita;Stuart,LyndaM;Orr,MarkT;Rawlings,DavidJ;Jackson,ShaunW;Lacy-Hulbert,Adam;Acharya,Mridu
• 通讯作者: Acharya,Mridu

β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage.

• DOI: 10.4049/jimmunol.1600244
• 发表时间: 2016-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Boucard-Jourdin M;Kugler D;Endale Ahanda ML;This S;De Calisto J;Zhang A;Mora JR;Stuart LM;Savill J;Lacy-Hulbert A;Paidassi H
• 通讯作者: Paidassi H