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（由申请方提供）：肺内的免疫应答严重依赖于主要组织相容性复合体（MHC）II类和CD 1分子的抗原呈递。 这些抗原呈递途径是哮喘和宿主防御感染的关键效应机制。 包括组织蛋白酶S在内的内体半胱氨酸蛋白酶在MHC II类和CD 1d的运输中起重要作用。缺乏组织蛋白酶活性的抗原呈递细胞（APC）不降解II类相关不变链（Ii），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也表现出CD 1 ld分子的异常内体运输，导致NK1.1+T细胞的选择缺陷。 这些数据暗示了MHC II类和CD 1d抗原呈递途径之间的相互作用，并表明半胱氨酸蛋白酶调节先天免疫和适应性免疫的组分。 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CD 1限制性抗原呈递，T细胞活化和肺部炎症。 为了研究这一假设，提出了三个具体目标。 第一个目标解决的假设，不同的半胱氨酸蛋白酶控制Ii蛋白水解和MHC II类在不同的APC功能。 这一假设将通过分析组织蛋白酶缺陷型APC中的Ii加工和II类依赖性抗原呈递来检验，所述组织蛋白酶缺陷型APC来源于包括肺在内的多种组织。 第二个目标将集中于研究组织蛋白酶缺陷型APC中II类-CD 1d相互作用的分子基础。 我们将讨论是否存在直接的II类-CD 1d分子关联，或者这些相互作用是否仅仅是广义内体运输缺陷的结果。 第三个目的是基于这样的前提，即组织蛋白酶活性的改变可以通过影响II类和CD 1d功能来调节肺免疫。 这些研究将使用基于卵清蛋白诱导的肺部炎症（Th 2型）的哮喘小鼠模型和结核分枝杆菌肺部感染（Th 1型）的小鼠模型。 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，并将确定这些酶的抑制是否会影响肺内MHC II类和CD 1依赖性炎症反应。