T-CELL ACTIVATION AND THYMIC TOLERANCE INDUCTION REQUIRE DIFFERENT ADHESION INTENSITIES OF THE CD8 CORECEPTOR

Activation of mature lymphocytes requires in addition to the TCR contact with the corresponding antigen the binding of the CD8 or CD4 co-receptors to MHC class I or class II proteins respectively. To investigate the contribution of the CD8 - class I interaction to the elimination of autoreactive T cells during negative selection in the thymus we generated two types of transgenic mice. One set expressed a modified K(b) Molecule which contained a human HLA-A2 alpha3 domain, thereby missing the binding residues for the murine CD8 molecules. The second set of mice expressed an anti-K(b) specific TCR. Both lines were crossed and in the resulting double transgenic mice the development of K(b)-reactive T cells was followed with an anti-clonotypic antibody. Surprisingly, efficient clonal deletion in the thymus was still observed, although the reduced CD8-class I adhesion abrogated effector functions in vivo and in vitro. These results imply that even T cells with intermediate affinity for self are negatively selected in the thymus despite the fact that they are not able to react against self antigens in the periphery. Thus a safety window is created which decreases the risk of autoaggression.