Cysteine Proteases in MHC Class II Antigen Presentation

内体半胱氨酸蛋白酶S在MHC II依赖免疫中起关键作用 通过其在降解MHCII相关的伴侣的作用，不变链(II)。但是，对 组织蛋白S-/-老鼠也发现了意想不到的发现。组织蛋白酶S缺乏主要影响Thl- 依赖豁免权。免疫球蛋白E反应和Th2驱动的肺部炎症，同时依赖半胱氨酸 在组织蛋白酶S-/-小鼠中，蛋白酶是正常的或增加的。事实上，基础IgE水平和肺组织中的mRNA 这些小鼠体内的促炎细胞因子升高。令人惊讶的是，高IgE水平和细胞因子是肥大的 依赖细胞。这些观察结果意味着更多的蛋白水解酶，或许还有更多的抗原呈递。 细胞(APC)，对MHCII功能很重要，蛋白酶失调可以扭曲，而不仅仅是阻断， 依赖MHCII的免疫反应。实验旨在了解蛋白水解酶如何 与肺部疾病相关的T和B细胞发育的效应极化。多肽在体内的载药机制 组织蛋白S缺乏的APC将被定义。II降解APC蛋白水解酶组织蛋白酶F缺陷的小鼠 最近产生的，将被用来检验组织蛋白酶F拯救MHC II类肽的假设 显示在髓系APC中，从而有利于Th2极化。选择性蛋白酶抑制剂将用于 确定变应原产生Th2细胞因子是否需要人APC中的一组蛋白酶活性- 刺激T细胞。肥大细胞促进APC依赖的IgE产生的机制将是 用S或细胞因子培养的肥大细胞重建肥大细胞缺陷小鼠的研究 有缺陷的小鼠。这项应用的总体目标是了解蛋白酶的分子基础- T细胞和B细胞免疫反应的依赖极化，并学习如何利用这一过程 改善自身免疫和哮喘等由CD4+T细胞引起的疾病。

The endosomal cysteine protease, cathepsin S, has a key role in MHC class II (MHCII)-dependent immunity through its role in degradation of the MHCII-associated chaperone, the invariant chain (Ii). But studies of cathepsin S -/- mice also reveal unexpected findings. Cathepsin S deficiency predominantly affects Thl- dependent immunity. IgE responses and Th2-driven pulmonary inflammation, while dependent on cysteine proteases, are normal or increased in cathepsin S -/- mice. Indeed baseline IgE levels and lung mRNA of proinflammatory cytokines in these mice are elevated. Surprisingly, high IgE levels and cytokines are mast cell-dependent. These observations imply additional proteases, and perhaps additional antigen presenting cells (APC), are important to MHCII function and that protease dysregulation can skew, not just block, MHCII-dependent immune responses. Experiments are directed toward understanding how proteases can effect polarization of T and B cell development relevant to lung disease. Mechanisms of peptide loading in cathepsin S-deficient APC will be defined. Mice deficient in the Ii-degrading APC protease cathepsin F have been recently generated and will be used to test the hypothesis that cathepsin F rescues MHC class II peptide display in myeloid APCs, thereby favoring Th2 polarization. Selective protease inhibitors will be used to determine if a set of protease activities in human APC are required for Th2 cytokine production by allergen- stimulated T cells. The mechanisms by which mast cells promote APC-dependent IgE production will be explored by reconstitution of mast cell deficient mice (Wsh) with mast cells cultured from S-/- or cytokine- deficient mice. The overall goal of this application is to understand the molecular basis for protease- dependent polarization of T cell and B cell immune responses and to learn how to exploit this process to ameliorate CD4+ T cell driven disorders such as autoimmunity and asthma.