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

描述(申请人提供)：CD4T细胞，特别是产生干扰素γ的Th1细胞，为细胞内病原体提供保护，如大利什曼原虫。相比之下，产生IL-4的Th2细胞没有保护作用，对这种病原体做出Th2主导反应的小鼠(和人类)对疾病高度敏感。不幸的是，对于为什么有些人在感染后不能做出保护性T细胞反应，我们的理解存在很大差距。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，我们还不知道是什么信号引导DC启动Th2的发育。在我们能够确定这些DC编程信号并了解它们如何改变DC的功能特性之前，开发能够对寄生虫(如利什曼原虫)或过敏原(如屋尘螨)“重定向”非保护性或致病性Th2反应的治疗方法的长期目标仍将是难以实现的。这项建议的主要目的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有能力在利什曼原虫感染后启动Th2反应所必需的，并确定我们是否可以操纵这些信号来诱导敏感品系的小鼠的免疫保护。这项研究的基本原理是，更好地了解DC是如何被病原体及其微环境中的细胞编程以诱导Th2发育的，将导致识别新的分子和信号通路，这些通路可能被利用来转移或抑制非保护性或致病性的Th2免疫反应。将被检验的中心假设是DC受到病原体和微环境的影响以获得Th2启动能力，并且干扰DC成熟过程中这两个条件步骤中的任何一个的药物可以用于防止对利什曼原虫的非保护性Th2反应的发展。检验这一假说的具体目标包括：(1)确定编程DC在重大利什曼原虫感染后表达CXCR5的内在和外部信号；(2)鉴定在表达CXCL13的LN微环境中提供的促进DC介导的Th2发育的细胞和分子调节信号；(3)确定我们是否通过调节CXCL13或淋巴毒素水平来改变利什曼病的进程。所提出的方法在概念上是创新的，因为我们正在超越目前以CCR7为中心的范例，以测试LN中的不同微域如何编程DC来启动Th2启动。此外，该提案是创新的，因为它将解决是否可以使用干扰这些CXCR5+DC在LN微环境中迁移的疗法来治疗对利什曼病敏感的小鼠品系。这项拟议的研究具有重要意义，因为它将极大地促进我们对DC如何获得启动Th2细胞的能力的理解，还因为它将确定可以有针对性地干预Th2介导的疾病的新途径，如无法治愈的进行性利什曼病、呼吸道合胞病毒和哮喘。

DESCRIPTION (provided by applicant): CD4 T cells, particularly IFNγ-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.