Cysteine Proteases in MHC Class II Antigen Presentation

内体半胱氨酸蛋白酶，组织蛋白酶S，在MHC II类（MHCII）依赖性免疫中具有关键作用 通过其在MHCII相关的分子伴侣不变链（Ii）的降解中的作用。但是， 组织蛋白酶S -/-小鼠也揭示了意想不到的发现。组织蛋白酶S缺乏主要影响Thl- 依赖性免疫IgE反应和Th 2驱动的肺部炎症，同时依赖于半胱氨酸 在组织蛋白酶S -/-小鼠中，蛋白酶是正常的或增加的。事实上，基线IgE水平和肺mRNA的 这些小鼠中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细胞， 依赖细胞的这些观察结果意味着额外的蛋白酶，可能还有额外的抗原呈递 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， MHCII依赖性免疫反应。实验旨在了解蛋白酶如何 影响与肺部疾病相关T和B细胞发育的极化。肽负载在 将定义组织蛋白酶S缺陷型APC。Ii降解APC蛋白酶组织蛋白酶F缺陷的小鼠具有 最近产生的，并将用于测试假设，组织蛋白酶F拯救MHC II类肽 在骨髓APC中显示，从而有利于Th 2极化。选择性蛋白酶抑制剂将用于 确定人APC中的一组蛋白酶活性是否是过敏原产生Th 2细胞因子所需的， 刺激T细胞。肥大细胞促进APC依赖性IgE产生的机制将是 通过用从S-/-或细胞因子- 缺陷小鼠本申请的总体目标是了解蛋白酶的分子基础- T细胞和B细胞免疫应答的依赖性极化，并学习如何利用这一过程， 改善CD 4 + T细胞驱动的疾病，如自身免疫和哮喘。

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.