Carboxypeptidase ACE and MHC Class I Presentation

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

? 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.