Using murine cytomegalovirus variants containing low and high avidity epitopes expressed by different promoters (strong/early vs weak/late), Borkner et al. demonstrate that low avidity epitopes can generate T-effector memory cells that are as protective as high avidity epitopes (but only when expressed in the strong/early context) and that competition between epitopes is impacted by both avidity and expression. Epitopes low in both parameters are driven to a non-protective T-central memory phenotype.
Experimental CMV-based vaccine vectors expressing a single MHC class I-restricted high-avidity epitope provided strong, T cell-dependent protection against viruses or tumors. In this study we tested the low-avidity epitope KCSRNRQYL, and show that a mouse CMV (MCMV) vector provides complete immune control of recombinant vaccinia virus expressing the same epitope if KCSRNRQYL is expressed within the immediate-early MCMV gene ie2 The same epitope expressed within the early M45 gene provided no protection, although MCMV vectors expressing the high-avidity epitope SSIEFARL induced protective immunity irrespective of gene expression context. Immune protection was matched by Ag-induced, long-term expansion of effector memory CD8 T cells, regardless of epitope avidity. We explained this pattern by observing regularities in Ag competition, where responses to high-avidity epitopes outcompeted weaker ones expressed later in the replicative cycle of the virus. Conversely, robust and early expression of a low-avidity epitope compensated its weak intrinsic antigenicity, resulting in strong and sustained immunity and immune protection.
Author Info: (1) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (2) Research Group Immune A
Author Info: (1) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (2) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (3) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (4) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (5) Institute for Virology, University Hospital Dusseldorf, Heinrich Heine University, 40225 Dusseldorf, Germany. (6) Institute for Virology, University Hospital Dusseldorf, Heinrich Heine University, 40225 Dusseldorf, Germany. (7) Research Group Immune Aging and Chronic Infections, Department of Vaccinology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; luka.cicin-sain@helmholtz-hzi.de. Institute for Virology, Medical School Hannover, 30625 Hannover, Germany; and. German Center for Infection Research, Hannover-Braunschweig Site, 38124 Braunschweig, Germany.
