Cyclosporin A blocks apoptosis by inhibiting the DNA binding activity of the transcription factor Nur77

Abstract

Engagement of T-cell receptors (TCRs) on immature thymocytes by self-antigen-major histocompatibility complexes causes the death of self-reactive thymocytes via apoptosis, a phenomenon that establishes T-cell tolerance. Similarly, treatment of thymocytes with anti-TCR antibodies leads to TCR-mediated apoptosis, which can also be induced in T-cell hybridomas. TCR-mediated apoptosis in immature thymocytes and T-cell hybridomas requires the expression of a new set of genes. In particular, it has recently been shown that the expression of Nur77, a transcription factor which is a member of the steroid/thyroid receptor superfamily, is required for TCR-mediated apoptosis in T-cell hybridomas and perhaps in thymocytes. Cyclosporin A (CsA), an immunosuppressive drug, has been shown to interfere with clonal deletion of self-reactive T cells in vivo, partly by blocking TCR-mediated apoptosis. We report here that CsA inhibits the TCR-mediated activation of Nur77 protein in T-cell hybridomas by blocking the DNA binding activity of Nur77 protein rather than its de novo synthesis. We also show that CsA mediates its negative effects on the Nur77 DNA binding activity through the N-terminal region of the protein. This complete inhibition of Nur77 protein DNA binding activity may explain how CsA interferes with TCR-mediated apoptosis.