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: 8843114
• 负责人: Adam Lacy-Hulbert
• 金额: $ 11.48万
• 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/8843114
• 关键词: Dendritic; Cell; Control; Intestinal; Responses

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 microrganisms 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. We are interested in the how Dendritic Cells (DCs) and other antigen presenting cells initiate and maintain the correct balance of T-helper cell subsets. Our long term goal is to understand how DCs distinguish normal from inflamed tissue and orchestrate appropriate immune responses. We have recently shown that T cell responses to TGF-¿, which is essential for Th17 cell development, requires activation of latent TGF-¿ mediated by a? integrins on DCs. Deletion of either 1v or the partner ¿8 chain in myeloid cells causes loss of both Th17 cells and Tregs in the intestine, leading to colitis. We hypothesize that DC expression of a?¿8 and subsequent activation of TGF-¿ controls induction and maintenance of Th17 responses. In this grant we propose to understand how av28 is regulated in DCs during Th17 responses. Using a?-conditional knockout mice we will test whether DC a? integrins are required for host defense against intestinal infections and for preventing Th17-mediated inflammatory disease. We will define the signals that regulate expression of a?¿8 in intestinal DCs and use cell biology and biochemical approaches to understand how a?¿8?-mediated TGF-¿ activation is regulated. Completion of the proposed aims 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）：肠上皮等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。研究表明，这些细胞亚群之间的平衡被破坏与结肠炎的发生密切相关。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。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和维持 T 辅助细胞亚群的正确平衡，并协调适当的免疫反应。 T 细胞对 TGF-¿ ，对于 Th17 细胞发育至关重要，需要激活潜在的 TGF-¿由 DC 上的整合素介导。 1v 或伴侣 ¿骨髓细胞中的 8 链会导致肠道中 Th17 细胞和 Tregs 的损失，从而导致结肠炎。 8 以及随后的 TGF-¿ 激活控制 Th17 反应的诱导和维持。在这项资助中，我们建议了解 Th17 反应期间 DC 中如何调节 av28，我们将测试 DC α 整合素是否是宿主防御肠道感染所必需的。预防 Th17 介导的炎症性疾病 我们将定义调节 a?¿ 表达的信号。 8 在肠道 DC 中，并使用细胞生物学和生化方法来了解如何？ 8?-介导的TGF-¿完成所提出的目标将为 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提供急需的了解。