Controlling Th2 immunity by tuning CXCL13 dependent DC migration in lymph nodes

描述（由申请人提供）：CD 4 T细胞，特别是产生IFN γ的Th 1细胞，为细胞内病原体如硕大利什曼原虫提供保护。相比之下，产生IL-4的Th 2细胞没有保护性，并且对这种病原体产生Th 2主导反应的小鼠（和人）对疾病高度易感。不幸的是，我们对为什么有些人在感染后不能产生保护性T细胞反应的理解存在重大差距。我们的数据表明，树突状细胞（DC）在这一过程中发挥了关键作用，但到目前为止，我们不知道是什么信号指导DC启动Th 2的发展。在我们能够识别这些DC编程信号并了解它们如何改变DC的功能特性之前，开发可以“重新定向”非保护性或致病性Th 2反应的治疗方法的长期目标仍然是难以捉摸的寄生虫，如利什曼原虫或过敏原，如屋尘螨。本提案的主要目标是确定感染组织和淋巴结（LN）中的关键信号，这些信号是使DC能够在利什曼原虫感染后启动Th 2应答所必需的，并确定我们是否可以操纵这些信号来诱导易感小鼠品系的免疫保护。拟议研究的基本原理是，更好地了解DC如何被病原体和其微环境中的细胞编程以诱导Th 2发育，将导致识别新的分子和信号通路，这些通路可能被用来转移或抑制非保护性或致病性Th 2免疫应答。将被测试的中心假设是，DC被病原体和微环境调节以获得Th 2引发能力，并且干扰DC成熟中的这些调节步骤中的任一个的药物可用于防止对利什曼原虫的非保护性Th 2应答的发展！本研究的具体目的包括：（1）确定DC在L.主要感染，（2）鉴定在表达CXCL 13的LN微环境中提供的细胞和分子调节信号，其促进DC介导的Th 2发育，和（3）确定我们是否通过调节CXCL 13或利什曼病毒素水平来改变利什曼病的病程。所提出的方法在概念上是创新的，因为我们正在超越当前以CCR 7为中心的范例来测试LN程序DC中的不同微域如何启动Th 2启动。此外，该提案是创新的，因为它将解决干扰LN微环境中这些CXCR 5 + DC迁移的治疗剂是否可用于治疗利什曼病易感小鼠品系。这项拟议的研究意义重大，因为它将大大推进我们对DCs如何获得启动Th 2细胞能力的理解，因为它将确定新的途径，可以靶向干预Th 2介导的疾病，如非治愈性进行性利什曼病，RSV和哮喘。

DESCRIPTION (provided by applicant): CD4 T cells, particularly IFN¿-producing Th1 cells, provide protection to intracellular pathogens like Leishmania major. By contrast, IL-4 producing Th2 cells are not protective and mice (and humans) that make a Th2- dominated response to this pathogen are highly susceptible to disease. Unfortunately, there are significant gaps in our understanding of why some individuals cannot make the protective T cell response upon infection. Our data suggests that dendritic cells (DCs) play a key role in this process, but to date, we do not know what signals direct the DCs to initiate Th2 development. Until we can identify these DC programming signals and understand how they change the functional properties of the DC, the long-term goal of developing therapeutics that can "re-direct" non-protective or pathogenic Th2 responses to parasites such as Leishmania or allergens like House Dust Mite will remain elusive. The major objectives of this proposal are to identify the key signals in the infected tissue and lymph node (LN) that are required to make DCs competent to initiate a Th2 response following Leishmania infection and to determine whether we can manipulate those signals to induce immune protection in susceptible strains of mice. The rationale for the proposed research is that a better understanding of how DCs are programmed by the pathogen and the cells within its microenvironment to induce Th2 development will lead to the identification of new molecular and signaling pathways that might be exploited to divert or suppress non-protective or pathogenic Th2 immune responses. The central hypothesis that will be tested is that DCs are conditioned by both the pathogen and the microenvironment to acquire Th2 priming capability and that drugs which interfere with either of these conditioning steps in DC maturation can be used to prevent the development of the non-protective Th2 response to Leishmania! The Specific Aims that will test this hypothesis include: (1) identifying the intrinsic and extrinsic signals that program DCs to express CXCR5 following L. major infection, (2) identifying the cellular and molecular conditioning signals provided within the CXCL13-expressing LN microenvironment which facilitate DC-mediated Th2 development and (3) determining whether we change the course of leishmaniasis by modulating CXCL13 or lymphotoxin levels. The proposed approach is conceptually innovative in that we are moving beyond the current CCR7-centric paradigm to test how different microdomains in the LN program DCs to initiate Th2 priming. In addition, the proposal is innovative in that it will addres whether therapeutics that interfere with the migration of these CXCR5+ DCs within the LN microenvironment can be used to treat Leishmania-susceptible strains of mice. The proposed research is significant because it will significantly advance our understanding of how DCs acquire the ability to prime Th2 cells and because it will identify new pathways that can be targeted to intervene in Th2-mediated diseases, like non-curing progressive Leishmanasis, RSV and asthma.