T cell activation and thymic tolerance induction require different adhesion intensities of the CD8 co-receptor.
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 Kb molecule which contained a human HLA-A2 alpha 3 domain, thereby missing the binding residues for the murine CD8 molecules. The second set of mice expressed an anti-Kb specific TCR. Both lines were crossed and in the resulting double transgenic mice the development of Kb-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.
Knobloch
M
M
Institute of Immunology and Genetics, German Cancer Research Center, Heidelberg.
Schönrich
G
G
Schenkel
J
J
Malissen
M
M
Malissen
B
B
Schmitt-Verhulst
A M
AM
Hämmerling
G J
GJ
Arnold
B
B
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D015551:Autoimmunity; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic / Q000276:immunology; D009368:Neoplasm Transplantation / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012641:Selection, Genetic; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D016827:CD8 Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins