Dendritic Cell Control of Intestinal T Cell Responses

描述（由申请方提供）：粘膜表面（如肠上皮）对免疫系统提出了复杂的挑战，因为它们必须对潜在病原体攻击保持有效的免疫力，同时还耐受肠道微生物和饮食抗原。耐受性和免疫性之间的平衡在很大程度上由特化T细胞群、调节性T细胞（TCLs）和Th 17细胞介导。通过对小鼠和人类的研究，这些亚群之间平衡的破坏与结肠炎的发生有很大关系。此外，Th 17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Th 17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。我们感兴趣的是树突状细胞（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。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。我们最近表明，T细胞对TGF-β的反应，这是必不可少的Th 17细胞的发展，需要激活潜在的TGF-β介导的？DC上的整合素。髓系细胞中1v或伴侣8链的缺失会导致肠道中Th 17细胞和Tcl 3细胞的丢失，导致结肠炎。我们假设，DC表达的一个？8和随后的TGF-β活化控制Th 17应答的诱导和维持。在这项研究中，我们提出了解在Th 17应答期间DC中av 28是如何调节的。使用？-条件性基因敲除小鼠我们将测试DC是否存在？整联蛋白是宿主防御肠道感染和预防Th 17介导的炎性疾病所必需的。我们将定义调节a？8在肠道DCs和使用细胞生物学和生物化学的方法来了解如何？八个？调节TGF-β介导的活化。所提出的目标的完成将提供一个急需的了解如何促进启动的树突状细胞在肠道中的Th 17细胞，并调节其随后的分化，以应对环境和感染的挑战。

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.