Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation

Nature. 1992 Jun 25;357(6380):695-7. doi: 10.1038/357695a0.


The immunosuppressive drugs cyclosporin A (CsA) and FK506 both interfere with a Ca(2+)-sensitive T-cell signal transduction pathway, thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro. We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cyclosporine / pharmacology
  • Gene Expression
  • Humans
  • Interleukin-2 / genetics
  • Lymphocyte Activation*
  • Mice
  • Models, Biological
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Promoter Regions, Genetic / drug effects
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • Tacrolimus / metabolism
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Proteins
  • Transfection


  • Calmodulin-Binding Proteins
  • Carrier Proteins
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Cyclosporine
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Tacrolimus Binding Proteins
  • Tacrolimus