Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc.
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 beta1 (TGF-beta1). We found that TGF-beta1 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-beta1. In parallel, TGF-beta1 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-beta1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-beta1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.
Genestier
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Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Kasibhatla
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Brunner
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Green
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000235:genetics; D006825:Hybridomas / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017252:CD3 Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; C016601:afimoxifene