Importance of MHC class I α2 and α3 domains in the recognition of self and non-self MHC molecules

The importance of the species of different domains of class I MHC molecules in peripheral T cell recognition and positive and negative selection was evaluated in a single system. In transgenic mice expressing AAD (containing the α1+α2 domains of HLA-A2.1 and the α3 domain of H-2D(d)), the CTL response to influenza peptide M1_58-66 in the context of the α1+α2 domains of HLA-A2.1 was as strong as the influenza-specific H-2D^b- restricted response. However, this strong response was only discernible if the target cell MHC molecule also contained a murine α3 domain. In contrast, the response in HLA-A2.1 transgenic mice was about 30-fold weaker, and these CTL were indifferent to the origin of the target molecule α3 domain. Further analysis suggested that the major impact of the murine α3 domain of the transgene product was to enhance positive selection of a low affinity population of AAD-restricted T cells, presumably through species-specific interaction with CD8. Surprisingly, the response to non-self human class I MHC determinants was not augmented in AAD mice, indicating that the T cells selected are narrowly focused on AAD-related structures. Further analysis indicated that the α1+α2 domains as well as the α3 domain influenced the magnitude of the response to non-self human class I MHC determinants, and this effect was mapped to α2. We suggest that the α2 domains of murine class I molecules contain conserved structural elements that augment the avidity of T cell-class I interactions, and this is particularly important in the recognition of non-self MHC molecules.