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Th17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，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。本申请的目的是确定DC如何调节T细胞对TGF-β的应答并控制Th17细胞分化。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，DC表达的<$v <$8和随后激活的TGF-β控制诱导和维持的Th17反应。基于已发表的工作和初步的数据，这一假设将在三个具体的目标进行测试：（1）确定DC表达的整合素如何调节Th17细胞分化，特别是IL 17/IFN-γ的产生。表达细胞 与自身免疫有关。条件性基因敲除小鼠将用于研究体内整合素的作用，结果将通过原代细胞培养扩展到人类。(2)了解在体内平衡调节和感染后，DCs中<$8的表达如何调节。(3)使用细胞生物学和生物化学方法确定DC上调节V 8功能的机制。这种方法是创新的，因为它专注于DC在“许可”T细胞对TGF-β的反应中的作用。拟议的工作是重要的，因为它将提供一个非常需要的了解如何DC促进肠道中的Th17细胞的启动，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 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.