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RESEARCH PRODUCT
Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors.
Niels A. W. LemmermannStephanie HoppeIryna DekhtiarenkoJennifer D. OduroLisa BorknerChristine MeyerLuka Cicin-sainRafaela HoltappelsKlaus FrühSonja FischerRenata BlatnikZsolt RuzsicsThomas F. MaranduJulia K. SonnemannMandana MansouriPaul KlenermanRobert B. RattsLian Ni LeeRamon ArensMatthias J. ReddehaseAngelika B. Riemersubject
0301 basic medicineMuromegalovirusEpitopes T-LymphocyteCD8-Positive T-LymphocytesLymphocyte ActivationPathology and Laboratory MedicineBiochemistryEpitopeMass SpectrometryMiceWhite Blood Cells0302 clinical medicineAnimal CellsMedicine and Health SciencesCytotoxic T celllcsh:QH301-705.5Antigens ViralImmune ResponseStainingVaccines SyntheticbiologyT CellsCell StainingHerpesviridae InfectionsFlow CytometryRecombinant Proteins3. Good healthmedicine.anatomical_structureMedical MicrobiologyViral PathogensVirusesHuman CytomegalovirusCellular TypesPathogensResearch Articlelcsh:Immunologic diseases. AllergyHerpesvirusesT cellImmune CellsAntigen presentationImmunologyCytotoxic T cellsMajor histocompatibility complexResearch and Analysis MethodsMicrobiology03 medical and health sciencesViral ProteinsImmune systemAntigenVirologyGeneticsmedicineAnimalsAntigen-presenting cellMolecular Biology TechniquesMolecular BiologyMicrobial PathogensBlood CellsImmunodominant EpitopesOrganismsBiology and Life SciencesProteinsViral VaccinesCell BiologyVirology030104 developmental biologylcsh:Biology (General)Specimen Preparation and Treatmentbiology.proteinMutagenesis Site-DirectedParasitologylcsh:RC581-607PeptidesDNA virusesImmunologic Memory030215 immunologyChromatography LiquidCloningdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-12-31 | PLoS pathogens |