Nature 357, 695 - 697 (25 June 1992); doi:10.1038/357695a0

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

Neil A. Clipstone & Gerald R. Crabtree

Beckman Center for Molecular and Genetic Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA

THE immunosuppressive drugs cyclosporin A (CsA) and FKS06 both interfere with a Ca²⁺-sensitive T-cell signal transduction pathway^1–4thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A)^1,5–7 involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors^8–10, 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 ¹²We 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.

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