ABSTRACT: BACKGROUND: Previous studies have defined vaccinia virus (VACV)-derived T cell epitopes in VACV-infected human leukocyte antigen-A*0201 (HLA-A2.1) transgenic (Tg) mice and A2.1-positive human Dryvax vaccinees. A total of 14 epitopes were detected in humans and 16 epitopes in A2.1 Tg mice; however, only two epitopes were independently reported in both systems. This limited overlap raised questions about the suitability of using HLA Tg mice as a model system to map human T cell responses to a complex viral pathogen. The present study was designed to investigate this issue in more detail. RESULTS: Re-screening the panel of 28 A2.1-restricted epitopes in additional human vaccinees and in A2.1 Tg mice revealed that out of the 28 identified epitopes, 13 were detectable in both systems, corresponding to a 46% concordance rate. Interestingly, the magnitude of responses in Tg mice against epitopes originally identified in humans is lower than for epitopes originally detected in mice. Likewise, responses in humans against epitopes originally detected in Tg mice are of lower magnitude. CONCLUSION: These data suggest that differences in immunodominance patterns might explain the incomplete response overlap, and that with limitations; HLA Tg mice represent a relevant and suitable model system to study immune responses against complex pathogens.