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

Iryna Dekhtiarenko, Robert B. Ratts, Renata Blatnik, Lian N. Lee, Sonja Fischer, Lisa Borkner, Jennifer D. Oduro, Thomas F. Marandu, Stephanie Hoppe, Zsolt Ruzsics, Julia K. Sonnemann, Mandana Mansouri, Christine Meyer, Niels A W Lemmermann, Rafaela Holtappels, Ramon Arens, Paul Klenerman, Klaus Frueh, Matthias J. Reddehase, Angelika B. RiemerLuka Cicin-Sain

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Article numbere1006072
JournalPLoS Pathogens
Volume12
Issue number12
DOIs
StatePublished - Dec 15 2016

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Dekhtiarenko, I., Ratts, R. B., Blatnik, R., Lee, L. N., Fischer, S., Borkner, L., Oduro, J. D., Marandu, T. F., Hoppe, S., Ruzsics, Z., Sonnemann, J. K., Mansouri, M., Meyer, C., Lemmermann, N. A. W., Holtappels, R., Arens, R., Klenerman, P., Frueh, K., Reddehase, M. J., ... Cicin-Sain, L. (2016). Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. PLoS Pathogens, 12(12), [e1006072]. https://doi.org/10.1371/journal.ppat.1006072