IMPORTANCE OF MHC CLASS-I ALPHA-2 AND ALPHA-3 DOMAINS IN THE RECOGNITION OF SELF AND NON-SELF MHC MOLECULES

The importance of the species of different domains of class I MHC mole cules in peripheral T cell recognition and positive and negative selec tion was evaluated in a single system. In transgenic mice expressing A AD (containing the alpha 1+alpha 2 domains of HLA-A2.1 and the alpha 3 domain of H-2D(d)), the CTL response to influenza peptide M1(58-66) i n the context of the alpha 1+alpha 2 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 a lso contained a murine alpha 3 domain, In contrast, the response in HL A-A2.1 transgenic mice was about 30-fold weaker, and these CTL were in different to the origin of the target molecule alpha 3 domain. Further analysis suggested that the major impact of the murine alpha 3 domain of the transgene product was to enhance positive selection of a low a ffinity population of AAD-restricted T cells, presumably through speci es-specific interaction with CD8. Surprisingly, the response to non-se lf human class I MHC determinants was not augmented in AAD mice, indic ating that the T cells selected are narrowly focused on AAD-related st ructures, Further analysis indicated that the alpha 1+alpha 2 domains as well as the alpha 3 domain influenced the magnitude of the response to non-self human class I MHC determinants, and this effect was mappe d to alpha 2. We suggest that the alpha 2 domains of murine class I mo lecules 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.