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Cyclosporin A Abolishes CD28-Mediated Resistance to CD95-Induced Apoptosis via Superinduction of Caspase-3¹

Andreas Kerstan^*,, Nicole Armbruster, Martin Leverkus^, and Thomas Hünig^2,*

^* Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany; Department of Dermatology, University of Würzburg, Würzburg, Germany; and Laboratory for Experimental Dermatology, Department of Dermatology and Venerology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

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 Ca²⁺ ionophores to TCR/CD28 or superagonistic CD28-stimulated cells reduced caspase-3 levels, further supporting a role for Ca²⁺-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Deutsche Forschungsgemeinschaft through the Graduiertenkolleg 520 Immunmodulation and Hu 295/8-1, and by TeGenero. M.L. was supported by Deutsche Forschungsgemeinschaft (Le 953 4/1) and Deutsche Krebshilfe (106849).

² Address correspondence and reprint requests to Dr. Thomas Hünig, Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg, Germany. E-mail address: huenig{at}vim.uni-wuerzburg.de

³ Abbreviations used in this paper: AICD, activation-induced cell death; CD95L, CD95 ligand; CDK4, cyclin-dependent kinase 4; CsA, cyclosporin A; pAb, polyclonal Ab; sCD95L, soluble CD95L; XIAP, X chromosome-linked inhibitor of apoptosis.

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