In summary, of the 28 epitopes identified in either humans or mice,
in this study we showed that 13 were detected in both systems, with an
overall concordance rate of 46% (Table 1).
This degree of overlap is, albeit incomplete, much greater than
previously detected. In a similar study, a 68% concordance rate was
observed between human immunodeficiency virus type 1 (HIV-1)-specific
CD8+ T cell epitopes recognized in both HLA-A2.1 Tg mice and HLA-A2 HIV-1 positive patients .
A higher degree of overlap was likely detected because HIV-1 epitope
recognition in A2.1 Tg mice was evaluated following peptide
immunization and not natural infection, a larger cohort of donors were
tested, and HIV-1 has a significantly smaller genome than VACV. These
data suggest that while the Tg mouse system is suitable to model immune
responses to complex pathogens, caution should be taken in interpreting
the results obtained.
Table 1. Summary of overlap between A2.1-restricted VACV T cell epitope recognition in HLA Tg mice and human systems
the more extensive and sensitive system used in the current study,
approximately one half of the epitopes recognized specifically in one
system were not recognized in the other. Differences in TCR repertoire
between mouse and human might account for the different epitope
recognition. However, peptide immunizations of the human epitopes in
A2.1 Tg mice only failed in 2 of 14 instances to generate a T cell
response. This is similar to the 85% success rate previously reported
by Wentworth et al. ,
and suggests that repertoire differences account for a relatively minor
percentage of the discrepancies. Differences in the processing
apparatus and antigen presentation in murine versus human dendritic
cell (DC) subsets and other antigen-presenting cells (APCs) involved in
priming CTL immunity might also explain the differential recognition of
some epitopes . In mice, multiple DC subsets have been described, however, CD8+ DCs are considered the primary DC subset involved in directly activating naïve CD8+ T cells during VACV infection . Recently, the CD8- DC subset has also shown to play an important role . In humans, various cell types are susceptible to VACV infection, including dermal DCs, Langerhans cells, and macrophages [23,24], but the primary APC responsible for naïve CD8+ T cell priming is unknown. As the peptides identified in the Tg mice were effectively processed in VACV-infected human APCs ,
differences in processing appear an unlikely explanation. Furthermore,
while mice were immunized i.p. and humans were vaccinated by dermal
scarification, we recently reported that either route generates similar
T cell responses, and only minor differences in magnitude of responses
were observed in mice .
Overall, our data suggest that while about half of the epitopes are
recognized both in humans and Tg mice, the actual magnitudes vary, and
thus differences in the immunodominance pattern contribute to the
degree of overlap in the responses observed. Discrepancies in the
kinetics of viral antigen expression in infected cells of human and
murine origin might impact immunodominance .
Interestingly, a recent study mapping HLA-A2.1-restricted epitopes
derived from modified VACV Ankara-infected human B cells by
differential HPLC-coupled mass spectrometry found epitopes
predominantly derived from early gene products .
However, we identified A2.1-restricted epitopes in HLA Tg mice and
human vaccinees from gene products expressed both early and late during
the viral life cycle . Despite having comparable T cell repertoires, the differences in immunodominance might be due to distinct naïve CD8+ T cell precursor frequencies in the two systems. We have recently demonstrated that precursor frequencies shape the CD8+ T cell immunodominance hierarchy following LCMV infection ,
and therefore this might also apply to a more complex virus, such as
VACV. These conclusions are in agreement with those drawn from a recent
study mapping the T cell responses in VACV-immune individuals, where it
was pointed out that an epitope might be considered immunodominant if
recognized by both humans and HLA Tg mice .
In summary, the present study suggests that, with limitations, HLA Tg
mice represent a relevant and suitable model system for identification
and validation of T cell epitopes recognized during the course of
complex viral infection in humans.