Cathepsins in Antigen Presentation and Lung Immunity

组织蛋白酶在抗原呈递和肺免疫中的作用

• 批准号: 7061391
• 负责人: MANUELA CERNADAS
• 金额: $ 40.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061391
• 关键词: Cathepsins; Antigen; Presentation; Lung; Immunity

DESCRIPTION (provided by applicant): The immune response within the lung is critically dependent on antigen presentation by the major histocompatibility complex (MHC) class II and CD1 molecules. These antigen presentation pathways are critical effector mechanisms in asthma and host defense against infection. Endosomal cysteine proteases, including cathepsin S, play important roles in trafficking of both MHC class II and CD1d. Antigen presenting cells (APC) devoid of cathepsin activity do not degrade class II-associated invariant chain (Ii) resulting in accumulation of endosomal class II-Ii complexes. Interestingly, APC from cathepsin S-deficient mice also exhibit abnormal endosomal trafficking of CD1ld molecules, resulting in defective selection of NK1.1+T cells. These data implicate an interaction between the MHC class II and CD1d antigen presentation pathways, and suggest that cysteine proteases regulate components of both innate and adaptive immunity. The central hypothesis of the proposed studies is that regulation of cathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CD1-restricted antigen presentation, T cell activation, and lung inflammation. To study this hypothesis three specific aims are advanced. The first aim addresses the hypothesis that different cysteine proteases control Ii proteolysis and MHC class II function in different APC. This hypothesis will be tested by analyzing Ii processing and class II-dependent antigen presentation in cathepsin-deficient APC, derived from a variety of tissues including the lung. The second aim will focus on examining the molecular basis for class II-CD1d interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD1d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect. The third aim is based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CD1d function. These studies will use a mouse model of asthma, based on ovalbumin-induced pulmonary inflammation (Th2-type), and a mouse model of mycobacterium tuberculosis pulmonary infection (Th1-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can affect MHC class II- and CD1-dependent inflammatory responses within the lung.

描述(申请人提供)：肺内的免疫反应严重依赖于主要组织相容性复合体(MHC)第二类和CD1类分子的抗原提呈。这些抗原提呈途径是哮喘和宿主抵抗感染的关键效应机制。内体半胱氨酸蛋白酶，包括组织蛋白酶S，在MHC-II和CD1d的转运中起着重要的作用。缺乏组织蛋白酶活性的抗原提呈细胞(APC)不会降解与II类相关的不变链(II)，从而导致内体II-II复合体的积聚。有趣的是，组织蛋白酶S缺陷小鼠的抗原原细胞也表现出CD11d分子的异常内体转运，导致NK1.1+T细胞的缺陷选择。这些数据暗示了MHC第二类和CD1d抗原呈递通路之间的相互作用，并表明半胱氨酸蛋白酶调节先天免疫和获得性免疫的组成部分。拟议研究的中心假设是，组织蛋白酶活性的调节，特别是组织蛋白酶S、L和F，将控制MHC II类和CD1限制性抗原提呈、T细胞激活和肺部炎症。为了研究这一假说，我们提出了三个具体目标。第一个目的是提出假设，不同的半胱氨酸蛋白酶在不同的APC中控制II类蛋白的降解和MHC II类的功能。这一假说将通过分析组织蛋白酶缺陷的APC中的II处理和II类依赖的抗原提呈来检验，APC来自包括肺在内的各种组织。第二个目标将集中于研究组织蛋白酶缺乏的APC中II类-CD1d相互作用的分子基础。我们将讨论是否存在直接的II类-CD1d分子关联，或者这些相互作用是否仅仅是普遍的内体运输缺陷的结果。第三个目的是基于这样一个前提，即组织蛋白酶活性的改变可以通过影响II类和CD1d功能来调节肺免疫功能。这些研究将使用基于卵蛋白诱导的肺部炎症的哮喘小鼠模型(Th2型)和结核分枝杆菌肺部感染的小鼠模型(Th1型)。总之，这些研究将探索半胱氨酸蛋白酶调节免疫的基本机制，并将确定抑制这些酶是否会影响肺内依赖MHC II和CD1的炎症反应。