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© The Rockefeller University Press, 0022-1007/1999/1/231/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 231-239

Articles

Transforming Growth Factor β1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc

Laurent Genestier, Shailaja Kasibhatla, Thomas Brunner, and Douglas R. Green

From the Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

Activation-induced cell death (AICD) is a process that regulates the size and the duration of the primary immune T cell response. In this report, we investigated the mechanisms involved in the regulation of AICD by transforming growth factor β1 (TGF-β1). We found that TGF-β1 decreased apoptosis of human T cells or T cell hybridomas after activation by anti-CD3. This decrease was associated with inhibition of Fas (Apo-1/CD95) ligand (FasL) expression, whereas Fas signaling was not affected by TGF-β1. In parallel, TGF-β1 inhibited c-Myc expression in T cell hybridomas, and ectopic expression of a chimeric molecule composed of c-Myc and the steroid binding domain of the estrogen receptor (Myc-ER) blocked both the inhibition of FasL and the decrease of AICD induced by TGF-β1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-β1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.

Key Words: apoptosis • T cells • transforming growth factor β • Fas ligand • c-myc

Address correspondence to Douglas R. Green, Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Rd., San Diego, CA 92121. Phone: 619-558-3500; Fax: 619-558-3526; E-mail: dgreen5240{at}aol.com

1 Abbreviations used in this paper: AICD, activation-induced cell death; AS, antisense; CDK, cyclin-dependent kinase; CsA, cyclosporine A; NF, nuclear factor; NS, nonsense; 4-OHT, 4-hydroxytamoxifen; RT, reverse transcription.

T. Brunner's present address is Division of Immunopathology, Institute for Pathology, University of Bern, 3010 Bern, Switzerland.


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