Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes
CD8+ T cells express T cell receptors (TCRs) that recognize short peptide antigens in the context of major histocompatibility class I (MHC I) molecules. This recognition process produces an array of cytokine-mediated signals that help to govern immunological responses. Design of biostable MHC I peptide vaccines containing unnatural subunits is desirable, and synthetic antigens in which a native α-amino acid residue is replaced by a homologous β-amino acid residue (native side chain but extended backbone) might be useful in this regard. We have evaluated the impact of α-to-β backbone modification at a single site on T cell-mediated recognition of six clinically important viral and tumor-associated antigens bound to an MHC I. Effects of this modification on MHC I affinity and T cell activation were measured. Many of these modifications diminish or prevent T cell response. However, a number of α/β-peptide antigens were found to mimic the activity of natural antigens or to enhance maximal T cell response, as measured by interferon-γ release. Results from this broad exploratory study advance our understanding of immunological responses to antigens bearing unnatural modifications and suggest that α/β-peptides could be a source of potent and proteolytically stable variants of native antigens.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:143 |
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| Enthalten in: |
Journal of the American Chemical Society - 143(2021), 17 vom: 05. Mai, Seite 6470-6481 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gibadullin, Ruslan [VerfasserIn] |
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| Links: |
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| Themen: |
Antigens, Neoplasm |
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| Anmerkungen: |
Date Completed 04.11.2021 Date Revised 06.05.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jacs.1c00016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324361912 |
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| 500 | |a Date Revised 06.05.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a CD8+ T cells express T cell receptors (TCRs) that recognize short peptide antigens in the context of major histocompatibility class I (MHC I) molecules. This recognition process produces an array of cytokine-mediated signals that help to govern immunological responses. Design of biostable MHC I peptide vaccines containing unnatural subunits is desirable, and synthetic antigens in which a native α-amino acid residue is replaced by a homologous β-amino acid residue (native side chain but extended backbone) might be useful in this regard. We have evaluated the impact of α-to-β backbone modification at a single site on T cell-mediated recognition of six clinically important viral and tumor-associated antigens bound to an MHC I. Effects of this modification on MHC I affinity and T cell activation were measured. Many of these modifications diminish or prevent T cell response. However, a number of α/β-peptide antigens were found to mimic the activity of natural antigens or to enhance maximal T cell response, as measured by interferon-γ release. Results from this broad exploratory study advance our understanding of immunological responses to antigens bearing unnatural modifications and suggest that α/β-peptides could be a source of potent and proteolytically stable variants of native antigens | ||
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| 650 | 7 | |a CTAG1B protein, human |2 NLM | |
| 650 | 7 | |a HLA-A2 Antigen |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Viral Matrix Proteins |2 NLM | |
| 650 | 7 | |a cytomegalovirus matrix protein 65kDa |2 NLM | |
| 700 | 1 | |a Randall, Caleb J |e verfasserin |4 aut | |
| 700 | 1 | |a Sidney, John |e verfasserin |4 aut | |
| 700 | 1 | |a Sette, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Gellman, Samuel H |e verfasserin |4 aut | |
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