Dendritic Cell Control of Intestinal T Cell Responses

描述(申请人提供)：肠上皮等粘膜表面对免疫系统构成了复杂的挑战，因为它们必须保持有效的免疫力，以抵御潜在的病原体攻击，同时还必须耐受共生微生物和饮食抗原。耐受和免疫之间的平衡在很大程度上是由特殊的T细胞群、调节性T细胞(Tregs)和Th17细胞调节的。通过对小鼠和人类的研究，这些亚群之间的平衡被严重破坏，导致结肠炎。此外，Th17细胞正在成为许多其他炎症性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)和其他抗原提呈细胞如何启动和维持T辅助细胞亚群的正确平衡。本应用的目的是确定DC如何调节T细胞对转化生长因子β的反应，并控制Th17细胞的分化。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v8和随后激活的转化生长因子-β控制Th17反应的诱导和维持。根据已发表的工作和初步数据，这一假说将在三个具体目标上得到验证：(1)确定DC表达的整合素如何调节Th17细胞的分化，特别是表达IL17/干扰素的细胞的产生 与自身免疫有关。条件基因敲除小鼠将被用于研究v整合素在体内的作用，结果将通过原代细胞培养扩展到人类。(2)了解在动态平衡调节期间和感染后DC中8的表达是如何调节的。(3)用细胞生物学和生物化学方法确定DC功能调节的机制。这种方法是创新的，因为它集中在DC在对转化生长因子-β的T细胞反应的‘许可’中的作用。这项拟议的工作意义重大，因为它将提供迫切需要的理解，了解DC如何促进肠道Th17细胞的启动，并调节它们随后的分化，以应对环境和感染挑战。 与公共卫生相关：肠道等粘膜部位的免疫反应受到严格调控，以防止对共生细菌的反应，但保持保护性免疫。这一规定的失效与许多炎症性疾病有关，包括炎症性肠病。细胞因子转化生长因子-β在这一调节中起主要作用，该项目的目标是了解免疫系统如何局部调节转化生长因子-β的活性，以产生保护性免疫，但防止炎症。

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.