Cyclosporin A abolishes CD28-mediated resistance to CD95-induced apoptosis via superinduction of caspase-3.
Costimulation of T cells via CD28 promotes both proliferation and resistance to apoptosis. In this study, we show that the immunosuppressive drug cyclosporin A (CsA) fully reverses resistance to CD95-mediated cell death after TCR/CD28 costimulation or superagonistic anti-CD28 mAb stimulation of primary rat lymph node T cells. This effect correlated with a pronounced superinduction of caspase-3 on both mRNA and protein levels, whereas its main antagonist, X chromosome-linked inhibitor of apoptosis, was unaffected by inclusion of CsA. Apoptosis triggered by CD95 cross-linking was characterized by robust caspase-3 activation. Furthermore, CsA sensitization to CD95-mediated apoptosis of CD28-activated T cells did not alter mRNA stability of superinduced caspase-3 mRNA, suggesting a transcriptional regulation of the caspase-3 gene. Addition of Ca(2+) ionophores to TCR/CD28 or superagonistic CD28-stimulated cells reduced caspase-3 levels, further supporting a role for Ca(2+)-dependent signaling pathways in negatively regulating caspase-3. Taken together, these findings suggest that CsA promotes sensitivity to CD95-mediated apoptosis in CD28-stimulated T cells by superinduction of the caspase-3 gene via a mechanism involving suppression of the calcineurin pathway.
Kerstan
Andreas
A
Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg, Germany.
Armbruster
Nicole
N
Leverkus
Martin
M
Hünig
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D019703:Calcineurin / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D007108:Immune Tolerance; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D016572:Cyclosporine; D019703:Calcineurin; D053148:Caspase 3