Cathepsins in Antigen Presentation and Lung Immunity

肺内的免疫反应严重依赖于大鼠的抗原提呈。 组织相容性复合体(MHC)II类和CD1分子。这些抗原提呈途径是至关重要的。 哮喘和宿主抵抗感染的效应机制。内体半胱氨酸蛋白酶，包括 组织蛋白S在MHC II类和CDLD的贩运中发挥了重要作用。抗原提呈细胞(APC) 缺乏组织蛋白酶活性不会降解与第II类相关的不变链(II)，从而导致 内体II-II类复合体。有趣的是，组织蛋白酶S缺陷小鼠的APC也表现出异常 CD1d分子的内体转运，导致NK1.1+T细胞的缺陷选择。这些数据表明 MHC-II和CD-L d抗原提呈通路之间的相互作用 蛋白水解酶调节天然免疫和获得性免疫的组成部分。建议中的中心假设 研究表明，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类 II和CDL限制性抗原提呈、T细胞激活和肺部炎症。研究这一点 假设提出了三个具体目标。第一个目标是提出假设，不同的半胱氨酸蛋白酶 控制II蛋白降解和MHC II类蛋白在不同的APC中发挥作用。这一假说将通过分析II来检验 多种组织来源的组织蛋白酶缺陷型APC的加工和II类依赖的抗原提呈 包括肺部。第二个目标将集中于研究第二类-CDLD相互作用的分子基础。 组织蛋白酶缺陷型APC。我们将讨论是否存在直接的II类-CD L d分子缔合，或者是否存在 这些相互作用完全是普遍的内体转运缺陷的结果。第三个目标是基于 组织蛋白酶活性的改变可能通过影响肺组织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(Th2型)的哮喘小鼠模型， 以及结核分枝杆菌肺部感染(THL型)的小鼠模型。总而言之，这些研究将 探讨半胱氨酸蛋白酶调节免疫的基本机制，并将决定是否抑制 这些酶中的一种可以影响肺内依赖MHC II类和CDL的炎症反应。

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 CDld. 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 CD ld molecules, resulting in defective selection of NK1.1 +T cells. These data implicate an interaction between the MHC class II and CD l d 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 ofcathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CDl-restricted antigen presentation, T cell activation, and lung inflannnation. 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-CDld interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD l d 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 CDld 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 (Thl-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can effect MHC class II- and CDl-dependent inflammatory responses within the lung.