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

Author:

Brunnberg Jamina1,Barends Martina1,Frühschulz Stefan1ORCID,Winter Christian1,Battin Claire2ORCID,de Wet Ben3ORCID,Cole David K.3,Steinberger Peter2ORCID,Tampé Robert1ORCID

Affiliation:

1. Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt am Main 60438, Germany

2. Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria

3. Immunocore Ltd., Abingdon OX14 4RY, United Kingdom

Abstract

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.

Funder

Deutsche Forschungsgemeinschaft

EC | ERC | HORIZON EUROPE European Research Council

Publisher

Proceedings of the National Academy of Sciences

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