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Dual role of the peptide-loading complex as proofreader and limiter of MHC-I presentation.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 28; Vol. 121 (22), pp. e2321600121. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
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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.<br />Competing Interests: Competing interests statement:B.W. and D.K.C. indicate a potential conflict of interest as former and present employee of Immunocore Ltd, respectively. The remaining authors declare no competing financial interests.
- Subjects :
- Humans
Calreticulin metabolism
Calreticulin genetics
Protein Disulfide-Isomerases metabolism
Protein Disulfide-Isomerases genetics
Receptors, Antigen, T-Cell metabolism
Receptors, Antigen, T-Cell immunology
Membrane Transport Proteins metabolism
Membrane Transport Proteins genetics
Endoplasmic Reticulum metabolism
Antigen Presentation immunology
Peptides metabolism
Peptides immunology
Histocompatibility Antigens Class I metabolism
Histocompatibility Antigens Class I genetics
Histocompatibility Antigens Class I immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 38771881
- Full Text :
- https://doi.org/10.1073/pnas.2321600121