Carboxypeptidase ACE and MHC Class I Presentation

 描述(由申请人提供)：主要组织相容性复合体(MHC)I类分子对多肽的表面呈递对于CD8+T细胞介导的肿瘤和病毒感染保护至关重要。科学家研究获得性免疫的一个主要目标是准确地了解细胞是如何产生其独特的免疫原性“肽指纹”的。这一建议是基于我们的新发现，即血管紧张素转换酶(ACE)是编辑MHC I类多肽C末端的主要羧基肽酶。初步数据显示，ACE基因敲除小鼠呈现出一种独特的I类多肽库，其中包含野生型小鼠没有的新抗原。此外，随着抗原提呈细胞的成熟，血管紧张素转换酶的表达增加，感染也会诱导血管紧张素转换酶表达。这些数据暗示了ACE在免疫挑战中的重要生理作用，包括CD8+T细胞对病毒感染的反应。本提案的主要目标是加深对羧基肽酶ACE参与MHC I类抗原处理的生化和生理方面的了解。鉴于服用ACE抑制剂的患者数量众多，这是一个重要的目标。具体地说，我建议(目标I)研究血管紧张素转换酶在产生MHC I类多肽方面的特异性。这一目的将检验ACE的生化特异性，以及ACE和蛋白酶体在产生MHC I类多肽过程中可能的协同作用。此外，还将评估ACE抑制剂在改变MHC-I类抗原提呈方面的作用。我还建议(目标II)研究ACE在抗原处理和对病毒感染的免疫反应中的生理作用。在这里，我将评估表达不同水平ACE的动物的病毒抗原提呈和病毒进展。特别是，我将确定ACE是否影响病毒衍生的免疫优势。这两个目标的实现不仅将扩大我们对抗原呈递的轻描淡写，而且可能提供新的靶点和策略来提高针对病原体感染和肿瘤的适应性免疫。

 DESCRIPTION (provided by applicant): The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell mediated protection from tumor and viral infection. A major goal of scientists studying adaptive immunity is to understand precisely how a cell generates it's unique immunogenic "peptide fingerprint". This proposal is based on our novel finding that angiotensin converting enzyme (ACE) is the major carboxypeptidase editing the C-termini of MHC class I peptides. Preliminary data show that ACE knockout mice present a distinctive class I peptide repertoire which contains novel antigens not present on wild-type mice. In addition, ACE expression is increased with the maturation of antigen presenting cells and also induced by infection. These data imply an important physiologic role for ACE during immunologic challenge, including the CD8+ T cell responses to viral infection. The overarching goal of the present proposal is to develop a deeper biochemical and physiological understanding of the involvement of the carboxypeptidase ACE in MHC class I antigen processing. Given the large number of patients taking ACE inhibitors, this is an important goal. Specifically, I propose (Aim I) to study the specificity of ACE in producing MHC class I peptides. This aim will examine the biochemical specificity of ACE and a possible synergy effect of ACE and proteasome in producing MHC class I peptides. Moreover, the effect of ACE inhibitor in changing MHC class I antigen presentation will be evaluated. I also propose (Aim II) to investigate the physiological roles of ACE in antigen processing and immune responses to viral infection. Here, I will evaluate viral antigen presentation and virus progressio in animals expressing different levels of ACE. In particular, I will determine whether ACE impacts the virus-derived immunodominance. The completion of both aims will not only broaden our understating of antigen presentation, but may provide novel targets and strategies to boost adaptive immunity against pathogenic infection and tumors.