Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621108
Title:
Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors.
Authors:
Dekhtiarenko, Iryna; Ratts, Robert B; Blatnik, Renata; Lee, Lian N; Fischer, Sonja; Borkner, Lisa; Oduro, Jennifer D; Marandu, Thomas F; Hoppe, Stephanie; Ruzsics, Zsolt; Sonnemann, Julia K; Mansouri, Mandana; Meyer, Christine; Lemmermann, Niels A W; Holtappels, Rafaela; Arens, Ramon; Klenerman, Paul; Früh, Klaus; Reddehase, Matthias J; Riemer, Angelika B; Cicin-Sain, Luka
Abstract:
Cytomegalovirus (CMV) elicits long-term T-cell immunity of unparalleled strength, which has allowed the development of highly protective CMV-based vaccine vectors. Counterintuitively, experimental vaccines encoding a single MHC-I restricted epitope offered better immune protection than those expressing entire proteins, including the same epitope. To clarify this conundrum, we generated recombinant murine CMVs (MCMVs) encoding well-characterized MHC-I epitopes at different positions within viral genes and observed strong immune responses and protection against viruses and tumor growth when the epitopes were expressed at the protein C-terminus. We used the M45-encoded conventional epitope HGIRNASFI to dissect this phenomenon at the molecular level. A recombinant MCMV expressing HGIRNASFI on the C-terminus of M45, in contrast to wild-type MCMV, enabled peptide processing by the constitutive proteasome, direct antigen presentation, and an inflation of antigen-specific effector memory cells. Consequently, our results indicate that constitutive proteasome processing of antigenic epitopes in latently infected cells is required for robust inflationary responses. This insight allows utilizing the epitope positioning in the design of CMV-based vectors as a novel strategy for enhancing their efficacy.
Citation:
Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. 2016, 12 (12):e1006072 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Dec-2016
URI:
http://hdl.handle.net/10033/621108
DOI:
10.1371/journal.ppat.1006072
PubMed ID:
27977791
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the research group immune aging and chronic infections (IMCI)

Full metadata record

DC FieldValue Language
dc.contributor.authorDekhtiarenko, Irynaen
dc.contributor.authorRatts, Robert Ben
dc.contributor.authorBlatnik, Renataen
dc.contributor.authorLee, Lian Nen
dc.contributor.authorFischer, Sonjaen
dc.contributor.authorBorkner, Lisaen
dc.contributor.authorOduro, Jennifer Den
dc.contributor.authorMarandu, Thomas Fen
dc.contributor.authorHoppe, Stephanieen
dc.contributor.authorRuzsics, Zsolten
dc.contributor.authorSonnemann, Julia Ken
dc.contributor.authorMansouri, Mandanaen
dc.contributor.authorMeyer, Christineen
dc.contributor.authorLemmermann, Niels A Wen
dc.contributor.authorHoltappels, Rafaelaen
dc.contributor.authorArens, Ramonen
dc.contributor.authorKlenerman, Paulen
dc.contributor.authorFrüh, Klausen
dc.contributor.authorReddehase, Matthias Jen
dc.contributor.authorRiemer, Angelika Ben
dc.contributor.authorCicin-Sain, Lukaen
dc.date.accessioned2017-09-15T07:54:32Z-
dc.date.available2017-09-15T07:54:32Z-
dc.date.issued2016-12-
dc.identifier.citationPeptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. 2016, 12 (12):e1006072 PLoS Pathog.en
dc.identifier.issn1553-7374-
dc.identifier.pmid27977791-
dc.identifier.doi10.1371/journal.ppat.1006072-
dc.identifier.urihttp://hdl.handle.net/10033/621108-
dc.description.abstractCytomegalovirus (CMV) elicits long-term T-cell immunity of unparalleled strength, which has allowed the development of highly protective CMV-based vaccine vectors. Counterintuitively, experimental vaccines encoding a single MHC-I restricted epitope offered better immune protection than those expressing entire proteins, including the same epitope. To clarify this conundrum, we generated recombinant murine CMVs (MCMVs) encoding well-characterized MHC-I epitopes at different positions within viral genes and observed strong immune responses and protection against viruses and tumor growth when the epitopes were expressed at the protein C-terminus. We used the M45-encoded conventional epitope HGIRNASFI to dissect this phenomenon at the molecular level. A recombinant MCMV expressing HGIRNASFI on the C-terminus of M45, in contrast to wild-type MCMV, enabled peptide processing by the constitutive proteasome, direct antigen presentation, and an inflation of antigen-specific effector memory cells. Consequently, our results indicate that constitutive proteasome processing of antigenic epitopes in latently infected cells is required for robust inflationary responses. This insight allows utilizing the epitope positioning in the design of CMV-based vectors as a novel strategy for enhancing their efficacy.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshAntigens, Viralen
dc.subject.meshCD8-Positive T-Lymphocytesen
dc.subject.meshChromatography, Liquiden
dc.subject.meshEpitopes, T-Lymphocyteen
dc.subject.meshFlow Cytometryen
dc.subject.meshHerpesviridae Infectionsen
dc.subject.meshImmunodominant Epitopesen
dc.subject.meshImmunologic Memoryen
dc.subject.meshLymphocyte Activationen
dc.subject.meshMass Spectrometryen
dc.subject.meshMiceen
dc.subject.meshMuromegalovirusen
dc.subject.meshMutagenesis, Site-Directeden
dc.subject.meshPeptidesen
dc.subject.meshVaccines, Syntheticen
dc.subject.meshViral Proteinsen
dc.subject.meshViral Vaccinesen
dc.titlePeptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors.en
dc.typeArticleen
dc.identifier.journalPLoS pathogensen

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