NF kappa B controls the balance between Fas and tumor necrosis factor cell death pathways during T cell receptor-induced apoptosis via the expression of its target gene A20.
Activation-induced cell death (AICD), a term originally coined for the anti-CD3-induced apoptosis of T cell hybridomas and thymocytes, is predominantly driven by death receptors and has been involved in the control of autoreactive T cells in the periphery. In the Do-11.10 T cell hybridoma model of AICD, activation of the T cell receptor (TCR) results in Fas-dependent apoptosis. Here, we show that inhibition of the transcription factor nuclear factor kappa B (NF kappa B) in Do-11.10 cells resulted in increased sensitivity to TCR-mediated apoptosis, correlating with defective induction of the anti-apoptotic NF kappa B target gene A20. Stable expression of the zinc finger protein A20 in NF kappa B-negative Do-11.10 cells rescued the phenotype. TCR activation in NF kappa B-deficient Do-11.10 cells resulted predominantly in tumor necrosis factor (TNF) receptor 2 (TNFR2)-dependent bystander cell death rather than classical Fas-dependent AICD. Strikingly, A20 blocked TNF-mediated apoptosis and simultaneously restored TCR-induced Fas-dependent AICD. In addition, NF kappa B downstream of TNFR was required for up-regulation of Fas expression by endogenous TNF secreted in response to TCR stimulation. Together, these results suggest that NF kappa B can play both pro- and anti-apoptotic roles during AICD. We propose that NF kappa B controls the balance between Fas and TNF cell death pathways during AICD via the expression of the zinc finger protein A20.
Malewicz
Michal
M
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany.
Zeller
Nicolas
N
Yilmaz
Z Buket
ZB
Weih
Falk
F
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D016923:Cell Death; D019281:Dimerization; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D005822:Genetic Vectors; D006825:Hybridomas / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D016335:Zinc Fingers; D019014:fas Receptor / Q000378:metabolism
D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor