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

• Published in: Nature (London) 1992-06, Vol.357 (6380), p.695-697
• Main Authors: Clipstone, Neil A, Crabtree, Gerald R
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Biological and medical sciences; Calcineurin; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; Carrier Proteins - metabolism; Cell Line; Cellular biology; Cyclosporine - pharmacology; Drugs; Enzymes; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Genetics; Humanities and Social Sciences; Humans; Immunity (Disease); Immunobiology; Interleukin-2 - genetics; letter; Lymphocyte Activation; Lymphocytes; Medical research; Mice; Models, Biological; multidisciplinary; Organs and cells involved in the immune response; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Promoter Regions, Genetic - drug effects; Receptors, Antigen, T-Cell - immunology; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; T-Lymphocytes - immunology; Tacrolimus - metabolism; Tacrolimus - pharmacology; Tacrolimus Binding Proteins; Transfection
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/357695a0

THE immunosuppressive drugs cyclosporin A (CsA) and FKS06 both interfere with a Ca 2+ -sensitive T-cell signal transduction pathway 1–4 thereby 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 Ca 2+ /calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro 12 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.