Dendritic Cell Control of Intestinal T Cell Responses

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，因为它们必须保持对潜在病原体攻击的有效免疫，同时还要耐受共生微生物和膳食抗原。耐受性和免疫之间的平衡在很大程度上是由特化的T细胞群、调节性T细胞（Tregs）和Th17细胞介导的。通过对小鼠和人类的研究，这些亚群之间平衡的破坏与引起结肠炎有很大关系。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反应是如何启动和调节的，对于我们理解肠道免疫和慢性炎症性疾病至关重要。我们对树突状细胞（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感兴趣。我们的长期目标是了解dc如何区分正常组织和炎症组织，并协调适当的免疫反应。我们最近的研究表明，T细胞对Th17细胞发育至关重要的TGF-¿的反应需要激活由a？dc上的整合素。髓系细胞中1v或伴侣¿8链的缺失都会导致Th17细胞和肠道中treg细胞的缺失，从而导致结肠炎。我们假设a的DC表达式？TGF- 8和随后的激活控制Th17反应的诱导和维持。在本研究中，我们拟了解在Th17应答过程中av28是如何在DCs中调控的。使用?-条件敲除小鼠，我们将测试DC a？整合素是宿主防御肠道感染和预防th17介导的炎症性疾病所必需的。我们将定义调节a？并使用细胞生物学和生化方法来了解肠道dc是如何发生的？介导的TGF-激活受到调节。完成所提出的目标将提供非常需要的理解dc如何促进Th17细胞在肠道中的起始并调节其随后的分化以应对环境和感染挑战。

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.