Dual role of the peptide- loading complex as proofreader and limiter of MHC- I presentation

• 成果类型: Article
• 署名作者: Brunnberg, Jamina; Barends, Martina; Fruehschulz, Stefan; Winter, Christian; Battin, Claire; de Wet, Ben; Cole, David K.; Steinberger, Peter; Tampe, Robert
• 署名单位: Goethe University Frankfurt; Medical University of Vienna
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9316
• DOI: 10.1073/pnas.2321600121
• 发表日期: 2024-05-28
• 关键词: major histocompatibility complex; t-cell-receptors; antigen presentation; immune-responses; situ detection; tapasin; molecules; hla; aminopeptidase; chaperone

摘要

Antigen presentation via major histocompatibility complex class I (MHC- I) molecules is essential for surveillance by the adaptive immune system. Central to this process is the peptide- loading complex (PLC), which translocates peptides from the cytosol to the endoplasmic reticulum and catalyzes peptide loading and proofreading of peptide- MHC- I (pMHC- I) complexes. Despite its importance, the impact of individual PLC components on the presented pMHC- I complexes is still insufficiently understood. Here, we used stoichiometrically defined antibody-nanobody complexes and engineered soluble T cell receptors (sTCRs) to quantify different MHC- I allomorphs and defined pMHC- I complexes, respectively. Thereby, we uncovered distinct effects of individual PLC components on the pMHC- I surface pool. Knockouts of components of the PLC editing modules, namely tapasin, ERp57, or calreticulin, changed the MHC- I surface composition to a reduced proportion of HLA- A*02:01 presentation compensated by a higher ratio of HLA- B*40:01 molecules. Intriguingly, these knockouts not only increased the presentation of suboptimally loaded HLA- A*02:01 complexes but also elevated the presentation of high- affinity peptides overexpressed in the cytosol. Our findings suggest that the components of the PLC editing module serve a dual role, acting not only as peptide proofreaders but also as limiters for abundant peptides. This dual function ensures the presentation of a broad spectrum of antigenic peptides.