Ir1 Genes, Peripheral Cross-Tolerance and Immunodominance in MHC Class I-Restricted T-Cell Responses: An Old Quagmire Revisited

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Abstract
Previous studies have shown that peripheral tolerance of one MHC molecule may influence the ability of an animal to respond to a particular antigenic determinant in the context of another MHC molecule (cross-tolerance). We describe here an investigation of the extent to which the presence of MHC molecules other than the one involved in Tc cell recognition affected whether or not a particular "antigen" (MHC/peptide) was recognized during the response of mice to infection with the flavivirus, West Nile (WNV). WNV-immune Tc cells from intra-H-2 recombinant mouse strains and F1 hybrid animals were used. In general, the antigens identified as immunogenic for five prototype mouse strains were immunogenic wherever the F1 or recombinant animal possessed the required MHC gene, but there were several notable exceptions. Firstly, while no responses were associated with Kd and Dk in BALB/c (H-2d) and CBA/H (H-2k) mice, respectively, in C3H.OH mice (Kd, Dk) both of these MHC molecules were associated with detectable responses. Secondly, in B10.A(2R) (Kk, Db) mice responses restricted by Db were not found whereas they were present in B6 mice (Kb, Db). This phenomenon was similar to previously reported phenomena with H-Y, Sendai, influenza and VV. However, it differed in two important ways. Firstly, we have no definitive evidence as yet that peripheral cross-tolerance to Kk influences responses against Db plus flavivirus as it does with H-Y and VV. Secondly, in addition to Kk, genes in the H-2s, H-2q and H-2d haplotypes influence responses to Db plus flavivirus but not responses to the other "antigens" listed above. Alternatively, the data are compatible with the concept of "immunodominance" based on a hierarchy of affinities of TCR's. the responding T-cell population appeared to focus the immune response on a limited number of "antigens"; in the presence of certain more strongly immunogenic "antigens", responses to other apparently more weakly immunogenic "antigens" were not seen.