Real time detection of peptide–MHC dissociation reveals that improvement of primary MHC-binding residues can have a minimal, or no, effect on stability

Miles, Kim M., Miles, John J., Madura, Florian, Sewell, Andrew K., and Cole, David K. (2011) Real time detection of peptide–MHC dissociation reveals that improvement of primary MHC-binding residues can have a minimal, or no, effect on stability. Molecular Immunology, 48 (4). pp. 728-732.

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The majority of known major histocompatibility complex class I (MHCI)-associated tumor-derived peptide antigens do not contain an optimal motif for MHCI binding. As a result, anchor residue-modified 'heteroclitic' peptides have been widely used in therapeutic cancer vaccination trials in order to enhance immune responsiveness. In general, the improved stability of these heteroclitic complexes has been inferred from their improved immunogenicity but has not been formally assessed. Here, we investigated the binding of 4 HLA A*0201-restricted tumor-derived peptides and their commonly used heteroclitic variants. We utilized a cell surface binding assay and a novel robust method for testing the durability of soluble recombinant pMHCI in real time by surface plasmon resonance. Surprisingly, we show that heteroclitic peptides designed with optimal MHC binding motifs do not always form pMHCs that are substantially more stable than their wildtype progenitors. These findings, combined with our recent discovery that TCRs can distinguish between wildtype peptides and those altered at a primary buried MHC anchor residue, suggest that altered TCR binding may account for a large part of the increased immune response that can be generated by anchor residue-modified ligands. Our results further highlight the fact that heteroclitic peptide-based immune interventions require careful evaluation to ensure that wildtype antigen specificity is maintained in vivo.

Item ID: 45233
Item Type: Article (Research - C1)
ISSN: 1872-9142
Keywords: surface plasmon resonance (SPR); peptide–major histocompatibility complex (pMHC); heteroclitic anchor residue-modified peptide; pMHC stability; T-cells; cancer vaccines
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© 2010 Elsevier Ltd. Open Access funded by Wellcome Trust under a Creative Commons license:

Funders: Royal Society (RS), Biotechnology and Biological Sciences Research Council (BBSRC), Leverhulme Trust (LT), UK, Tenovus Foundation (TF), National Health and Medical Research Council (NHMRC), Wales Office of Research and Development (WORD), Wellcome Trust (WT)
Projects and Grants: RS RG080077, BBSRC BB/H001085/1
Date Deposited: 23 Aug 2016 01:47
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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