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

PLoS Pathogens

Zsolt Ruzsics¹  Matthias J. Reddehase²  Stephanie Hoppe³  Niels A. W. Lemmermann³  Jennifer D. Oduro³  Iryna Dekhtiarenko³  Lisa Borkner³  Thomas F. Marandu³  Renata Blatnik⁴  Julia K. Sonnemann⁴  Paul Klenerman⁵  Klaus Früh⁵  Christine Meyer⁶  Mandana Mansouri⁷  Lian N. Lee⁷  Angelika B. Riemer⁸  Sonja Fischer⁸  Luka Cicin-Sain⁹  Robert B. Ratts⁹  Ramon Arens⁹  Rafaela Holtappels^1,10 

[1] Dar es Salaam University College of Education, Dar es Salaam, Tanzania;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands;Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Immunotherapy and prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany;Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany;Institute for Virology, University Medical Center Freiburg, Freiburg, Germany;Molecular Vaccine Design, German Center for Infection Research (DZIF), Heidelberg, Germany;Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;TomegaVax Inc., Portland, Oregon, United States of America;Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America

关键词: T cells;    Cytotoxic T cells;    Immune response;    Cloning;    Human cytomegalovirus;    Cell staining;    Antigen-presenting cells;    Recombinant proteins;   

DOI  :  10.1371/journal.ppat.1006072

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY