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In the course of viral infection, the immune system exploits only a fraction of the available CTL repertoire and focuses on a few of a myriad of potentially antigenic peptides. This phenomenon, known as immunodominance, depends on a number of factors, including antigen processing and transport, MHC binding, competition for antigen-presenting cells, availability of the CD8 T cell repertoire and other mechanisms that function largely by restricting the immune response. Here we elucidate a novel mechanism that increases the immunodominance of the epitope rather by enhancing the immune response. Using a peptide-specific MHC-restricted mAb and functional assays of CTL activation, we show that T cells with high avidity for the immunodominant, H-2Dd restricted, P18-I10 epitope expand rapidly following immunization, and this expansion in turn determines the level of the P18-I10 epitope immunodominance. This proliferation has little dependence on the number of MHC–peptide complexes. Since most self-reactive T cells of high avidity are depleted in the thymus, the selection of immunodominant epitopes based on the expansion of high-avidity T cells in the periphery reduces the potential for autoimmunity. [ABSTRACT FROM AUTHOR]

CD8 can serve as a co-receptor or accessory molecule on the surface of CTL. As a co-receptor, CD8 can bind to the α3 domain of the same MHC class I molecules as the TCR to facilitate TCR signaling. To evaluate the role of the MHC class I molecule α3 domain in the activation of CD8+ CTL, we have produced a soluble 227 mutant of H-2Dd, with a point mutation in the α3 domain (Glu227→Lys). 227 mutant class I–peptide complexes were not able to effectively activate H-2Dd-restricted CD8 T cells in vitro, as measured by IFN-γ production by an epitope-specific CD8+ CTL line. However, the 227 mutant class I–peptide complexes in the presence of another MHC class I molecule (H-2Kb) (that cannot present the peptide) with a normal α3 domain can induce the activation of CD8+ CTL. Therefore, in order to activate CD8+ CTL, the α3 domain of MHC class I does not have to be located on the same molecule with the α1 and α2 domains of MHC class I. A low-avidity CD8+ CTL line was significantly less sensitive to stimulation by the 227 mutant class I–peptide complexes in the presence of the H-2Kb molecule. Thus, low-avidity CTL may not be able to take advantage of the interaction between CD8 and the α3 domain of non-presenting class I MHC molecules, perhaps because of a shorter dwell time for the TCR–MHC interaction. [ABSTRACT FROM AUTHOR]