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These data suggest that differences in immunodominance patterns might explain the incomplete …

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- Of mice and humans: how good are HLA transgenic mice as a model of human immune responses?

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 [20]. 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

Despite 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. [4], 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 [7]. 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 [21]. Recently, the CD8- DC subset has also shown to play an important role [22]. 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 [5], 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 [25].

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 [26]. 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 [27]. 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 [28]. 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 [29], 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 [30]. 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.

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