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

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.

Figure 1

Testing A2.1-restricted VACV T cell epitopes in A2.1 Tg mice using purified CD8⁺ T cells and individual peptides. (A) Splenic CD8⁺ cells were purified from VACV-infected A2.1 Tg mice and incubated with peptide-pulsed Jurkat-A2.1/K^b cells, after which number of IFN-γ-producing cells was enumerated in an ELISPOT assay. Shown are the average net SFC/10⁶ CD8⁺ T cells in response to each peptide; black bars, epitopes identified by Oseroff et al. [9] in A2.1 positive donors and recognized in Tg mice upon re-screening; white bars, peptides identified by Pasquetto et al. [5] in Tg mice; grey bars, epitopes identified in both studies. (B) The specific T cell response to three different epitopes (B14R_327–335, M1L_374–383, and A14L_51–59) was assessed 7 days after VACV infection in A2.1 Tg mice. Shown is the stimulation index for the epitopes tested either as individual peptides (black bars) or in pools of ten peptides (white bars). (C) Shown is the stimulation index for the epitope-specific responses by using either CD8⁺ T cells (black bars) or splenocytes (white bars). (D) Shown are the average net SFC/10⁶ CD8⁺ T cells in response to groups of epitopes recognized in Tg mice upon re-screening (black bar) and identified in Tg mice in the original study by Pasquetto et al. [5] (white bar). The unpaired t test with Welch's correction was used to determine if differences were significant. For all panels, average data are shown from at least two independent experiments. For each individual experiment samples are tested in triplicate. Error bars indicate SEM.