We have described the CD8+ T cell response to two dominant epitopes, Kd
(Kulkarni et al., 1993
; Rutigliano et al., 2005
), in RSV-infected H-2d/b hybrid CB6F1/J mice where the consequences of epitope competition on the T cell response can be independently studied. These mice have been used previously to study the hybrid resistance effect in LCMV infection (Doherty and Allan, 1986a
). We suggest that the hybrid mouse model provides a system to define the rules of epitope hierarchy and to better understand the determinants of CD8+ T cell effector functions. The system allows for adoptive transfer of cells from either parent strain into the hybrid mouse to define the role of antigen presentation or CD4+ T cell help on determining the functional characteristics of epitope-specific CD8+ T cell responses. It provides a system to address whether patterns of epitope hierarchy can be modified by vaccination or the conditions under which antigen presentation occurs. In addition, sorting and clonotyping epitope-specific T cells following vaccination or RSV infection will augment our understanding of how clonal selection and TCR clonotype patterns influence CD8+ T cell phenotypes. These questions are under active investigation in our laboratory.
Despite exhibiting dominance in parent C57Bl/6 mice, the Db
epitope became subdominant to the Kd
epitope in H-2d/b mice. It has previously been shown that there is no haplotype preference in H-2d/b
mice (Thomsen and Marker, 1989
). However, another study that looked at CB6F1/J chimeras infected with Listeria monocytogenes
strain EJL243, which co-expresses the secreted LCMV NP protein, also showed that the H2-Kd
–restricted response was dominant compared to the H2-Db
-restricted response (Lenz et al., 2000
). Evaluation of relative MHC class I expression in F1 hybrid mice suggested that H-2b
MHC class I molecules are similarly expressed on the cell surface in H-2b/d
mice, although the mixing of alleles in other F1 hybrids may result in unequal expression (Tourdot and Gould, 2002
), and epitope-specific effects may occur. Studies from Harty et. al. have shown that CD8+ T cell contraction may be preprogrammed and controlled by early inflammation (Badovinac et al., 2002
). Similarly, it has recently been proposed by Doherty’s group that clonal expansion of CD8+ T cells in response to certain influenza epitopes may ensue from a preset pattern (Thomas et al., 2006
). Our studies, combined with the recent description of minor Db
-restricted epitopes (Lukens et al., 2006
), may provide a system to help define the principles underlying CD8+ T cell response patterns after RSV infection or immunization.
Interestingly, we found that although the DbM187–195 response was quantitatively subdominant in CB6F1/J hybrid mice, almost all M187–195 -specific cells produce IFN-γ after peptide stimulation. In contrast, only a fraction of KdM282–90-specific cells produce IFN-γ after stimulation. During primary infection, DbM187–195-specific cells also produce more IFN-γ per cell than KdM282–90-specific as measured by MFI. These differences are not maintained in the memory phase, where the M2 response is both quantitatively and functionally dominant. These data suggest that the more functionally active DbM187–195-specific cells may have the capacity for effector function during primary infection, but less often survive into the memory phase. Using the hybrid mouse model to further define ancillary responses and host factors involved in establishing epitope hierarchy, and the function of epitope-specific cells, will help establish the contribution of subdominant T cell epitopes in viral pathogenesis and potentially inform T cell-based vaccine design.