Carboxypeptidase ACE and MHC Class I Presentation

 描述（由申请方提供）：主要组织相容性复合体（MHC）I类分子对肽的表面呈递对于CD 8 + T细胞介导的保护免受肿瘤和病毒感染至关重要。科学家研究适应性免疫的一个主要目标是精确地了解细胞如何产生其独特的免疫原性“肽指纹”。这个建议是基于我们的新发现，血管紧张素转换酶（ACE）是主要的羧肽酶编辑的C-末端的MHC I类肽。初步数据显示，ACE敲除小鼠呈现出独特的I类肽库，其中含有野生型小鼠上不存在的新抗原。此外，ACE的表达随着抗原呈递细胞的成熟而增加，并且也由感染诱导。这些数据表明，ACE在免疫挑战，包括CD 8 + T细胞对病毒感染的反应的重要生理作用。本提案的总体目标是发展一个更深层次的生化和生理的理解参与的羧肽酶ACE在MHC I类抗原加工。鉴于大量患者服用ACE抑制剂，这是一个重要的目标。具体而言，我建议（目的I）研究ACE在生产MHC I类肽的特异性。这一目的将检查ACE的生化特异性和ACE和蛋白酶体在产生MHC I类肽中可能的协同作用。此外，还将评价ACE抑制剂在改变MHC I类抗原呈递方面的作用。我还建议（目的II）研究ACE在抗原加工和病毒感染的免疫反应中的生理作用。在这里，我将评估病毒抗原呈递和病毒进展在动物表达不同水平的ACE。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拓宽我们对抗原呈递的理解，而且可能提供新的靶点和策略来增强针对病原性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.