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: 6698103
• 负责人: RICHARD J RIESE
• 金额: $ 41.06万
• 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/6698103
• 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（由申请人提供）：肺内的免疫反应严重取决于主要的组织相容性复合物（MHC）II类和CD1分子的抗原表现。 这些抗原呈递途径是哮喘中的关键效应机制和宿主防御感染。 包括组织蛋白酶在内的内体半胱氨酸蛋白酶在贩运MHC II和CD1D中起着重要作用。缺乏组织蛋白酶活性的抗原呈递细胞（APC）不会降低与II类相关的不变链（II），从而导致内体II-II类复合物的积累。 有趣的是，来自组织蛋白酶S缺陷小鼠的APC还表现出CD1LD分子的异常内体运输，从而导致选择有缺陷的NK1.1+T细胞。 这些数据暗示了MHC II类和CD1D抗原呈现途径之间的相互作用，并表明半胱氨酸蛋白酶调节先天和适应性免疫的成分。 拟议的研究的中心假设是，组织蛋白酶活性（尤其是组织蛋白酶S，L和F）的调节将控制MHC II类和CD1限制的抗原表现，T细胞激活和肺部炎症。 为了研究这一假设，三个具体目标是提前的。 第一个目的解决了以下假设：不同的半胱氨酸蛋白酶控制II蛋白水解和MHC II类在不同APC中的功能。 该假设将通过分析源自组织蛋白酶缺陷的APC中的II加工和II类依赖性抗原表现来检验，该抗原的APC来自包括肺在内的多种组织。 第二个目的将集中于检查组织蛋白酶缺陷型APC中II类CD1D相互作用的分子基础。 我们将解决是否存在直接的II-CD1D分子关联，还是这些相互作用仅仅是广义内体贩运缺陷的结果。 第三个目的是基于这样的前提：组织蛋白酶活性的改变可以通过对II类和CD1D功能的影响来调节肺免疫。 这些研究将基于卵巢蛋白诱导的肺部炎症（Th2型）和结核分枝杆菌肺部感染（TH1型）的小鼠模型，使用哮喘的小鼠模型。 总之，这些研究将探测半胱氨酸蛋白酶调节免疫的基本机制，并确定对这些酶的抑制是否会影响肺内MHC II类和CD1依赖性炎症反应。