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: 8372489
• 负责人: Adam Lacy-Hulbert
• 金额: $ 35.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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/8372489
• 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; Interferons; Interleukin-17; Intestines; Knockout Mice; Licensing; Link; Maintenance; Mediating; Modeling; 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; Stimulus; Surface; T cell response; T-Lymphocyte; Testing; Th1 Cells; 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-¿ 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 ¿v¿8 and subsequent activation of TGF-¿ 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 ¿v integrins expressed by DCs regulate Th17 cell differentiation, particularly the generation of IL17/ IFN-?-expressing cells associated with autoimmunity. Conditional knockout mice will be used to study the role for ¿v integrins in vivo, and results will be extended to humans though primary cell culture. (2) Understand how ¿8 expression is regulated in DCs during homeostatic regulation and following infection. (3) Determine the mechanisms by which ¿v¿8 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-¿. 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. PUBLIC HEALTH RELEVANCE: Immune responses at mucosal sites such as the intestine are tightly regulated to prevent reactions to commensal bacteria but maintain protective immunity. Breakdown in this regulation has been linked to many inflammatory diseases, including inflammatory bowel disease. The cytokine TGF-¿ plays a major role in this regulation and the goal of this project is to understand how TGF-¿ activity is locally regulated by the immune system to generate protective immunity but prevent inflammation.

描述（由应用提供）：粘膜表面（例如肠上皮）为免疫系统提供了复杂的挑战，因为它们必须维持对潜在病原体攻击的有效免疫组织化学，同时还可以耐受共生微生物和饮食抗原。耐受性和免疫组织化学之间的平衡在很大程度上是由专业的T细胞群，调节性T细胞（Treg）和TH17细胞介导的。这些子集之间平衡的破坏已经很大程度上涉及通过对小鼠和人类的研究引起结肠炎。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，了解如何启动和调节Th17反应对于我们对肠道免疫学和慢性炎症性疾病的理解至关重要。我们的长期目标是了解树突状细胞（DC）和其他抗原呈递细胞如何启动并维持T-辅助细胞亚群的正确平衡。该应用程序的目的是确定DC如何调节T细胞对TGF- - 和控制TH17细胞分化的反应。这项工作的理由是，了解这一过程有可能转化为Th17介导的疾病的新疗法。我们的核心假设是»v¿8的直流表达以及随后TGF-€的激活控制Th17响应的诱导和维持。基于已发表的工作和初步数据，该假设将以三个特定的目的进行检验：（1）确定DC表达的V整联蛋白如何调节Th17细胞分化，尤其是IL17/ IFN的生成 - ？ 与自身免疫相关。有条件的敲除小鼠将用于研究体内的V整联蛋白的作用，结果将通过原代细胞培养扩展到人类。 （2）了解在稳态调节和感染后DC中如何调节8表达。 （3）确定使用细胞生物学和生化方法在DC上调节DC的机制。这种方法具有创新性，因为它着重于DC在“许可” T细胞对TGF-响应中的作用。拟议的工作很重要，因为它将非常需要了解DC如何促进肠道中Th17细胞的主动性，并根据环境和感染性挑战来调节其随后的分化。 公共卫生相关性：诸如肠道粘膜部位的免疫反应受到严格调节，以防止对共生细菌的反应，但保持受保护的免疫学。该法规中的细分与许多炎症性疾病有关，包括炎症性肠病。细胞因子TGF-在该调节中起着重要作用，该项目的目的是了解TGF- - 活性如何受到免疫系统的局部调节，以产生受保护的免疫组织化学，但可以防止炎症。