J. Exp. Med., Volume 189, Number 2, January 18, 1999 231-239

Transforming Growth Factor 1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc

By 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 1 (TGF-1). We found that TGF-1 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-1. In parallel, TGF-1 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-1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.

apoptosis;  T cells;  transforming growth factor ;  Fas ligand;  c-myc

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