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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]