Abstracts (complete list) - Wissenschaft Online

Gasteiger Georg, Kastenmuller Wolfgang, Sutter Gerd, Drexler Ingo
Exclusive cross-priming of cytotoxic T-cells dictates antigen
requisites for MVA vector vaccines
Viral vectors are evaluated as recombinant vaccines but little is known about the
antigen-presentation pathways that are important to induce efficient T-cell immunity
with these vectors. Many viruses can infect pAPCs resulting in direct presentation of
antigenic determinants. MHC-I-restricted cross-presentation of exogenous antigen,
however, can contribute to antiviral immunity. We confirm metabolic stability as a
critical factor for access of antigenic substrates for antigen-presenting pathways. We
analyzed vaccines based on the replication-deficient vaccinia virus MVA in two distinct
mouse models. Infection with MVA expressing the model antigens tyrosinase or
ovalbumin either targeted for rapid proteasomal degradation or expressed as minigenes
enhanced MHC-class-I/peptide presentation on DC as well as non-pAPC in vitro and in
vivo, but dramatically impaired CD8+ T-cell (TCD8+)priming. Similar results were
obtained when antigen presentation was restricted to cross-presentation in vivo
indicating that direct priming plays a minor role for TCD8+ induction. Additionally,
downregulation of cross-presentation by CpG-induced maturation of DC prior to
immunization abrogated TCD8+ priming, but did not affect infectivity rate, antigen
processing or direct priming of TCD8+ in vivo.
Our results show that MVA vaccines exclusively depend on TCD8+ cross-priming. This is
surprising, as we show that MVA easily infects DC and allows strong antigen
presentation by these pAPC in vivo. The data reveal new aspects concerning biological
properties of antigens that can be selected to induce strong T-cell immunity. Moreover,
we show that it is possible and necessary to adjust the target antigens to the intrinsic
requirements of the delivering vector with direct implications for the design of optimized
vaccines targeting TCD8+ responses in infectious disease and cancer. Recent clinical
studies suggest that our findings might also apply to humans.