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。本应用的目的是建立dc如何调节T细胞对TGF-¿的反应并控制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治疗th17介导疾病的新疗法。我们的中心假设是DC表达¿v¿8和随后TGF-¿的激活控制Th17反应的诱导和维持。基于已发表的工作和初步数据，这一假设将在三个具体目标中得到验证：(1)确定dc表达的整合素如何调节Th17细胞分化，特别是IL17/ IFN-的产生？表达的细胞

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.