K. Yazdanbakhsh et al., CYCLOSPORINE-A BLOCKS APOPTOSIS BY INHIBITING THE DNA-BINDING ACTIVITY OF THE TRANSCRIPTION FACTOR NUR77, Proceedings of the National Academy of Sciences of the United Statesof America, 92(2), 1995, pp. 437-441
Engagement of T-cell receptors (TCRs) on immature thymocytes by self-a
ntigen-major histocompatibility complexes causes the death of self-rea
ctive thymocytes via apoptosis, a phenomenon that establishes T-cell t
olerance, Similarly, treatment of thymocytes with anti-TCR antibodies
leads to TCR-mediated apoptosis, which can also be induced in T-cell h
ybridomas. TCR-mediated apoptosis in immature thymocytes and T-cell hy
bridomas requires the expression of a new set of genes, In particular,
it has recently been shown that the expression of Nur77, a transcript
ion factor which is a member of the steroid/thyroid receptor superfami
ly, is required for TCR-mediated apoptosis in T-cell hybridomas and pe
rhaps in thymocytes. Cyclosporin A (CsA), an immunosuppressive drug, h
as been shown to interfere with clonal deletion of self-reactive T Cel
ls in viva, partly by blocking TCR-mediated apoptosis, We report here
that CsA inhibits the TCR-mediated activation of Nur77 protein in T ce
ll hybridomas by blocking the DNA binding activity of Nur77 protein ra
ther than its de novo synthesis, We also show that CsA mediates its ne
gative effects on the Nur77 DNA binding activity through the N-termina
l region of the protein, This complete inhibition of Nur77 protein DNA
binding activity may explain how CsA interferes with TCR-mediated apo
ptosis.