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J. Biol. Chem., Vol. 278, Issue 35, 32825-32833, August 29, 2003

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NFB 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^*,

Michal Malewicz , Nicolas Zeller , Z. Buket Yilmaz and Falk Weih ¶

From the Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany

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 B (NFB) in Do-11.10 cells resulted in increased sensitivity to TCR-mediated apoptosis, correlating with defective induction of the anti-apoptotic NFB target gene A20. Stable expression of the zinc finger protein A20 in NFB-negative Do-11.10 cells rescued the phenotype. TCR activation in NFB-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, NFB 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 NFB can play both pro- and anti-apoptotic roles during AICD. We propose that NFB controls the balance between Fas and TNF cell death pathways during AICD via the expression of the zinc finger protein A20.

Received for publication, April 16, 2003 , and in revised form, June 12, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant We2224/1-1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Fig. 1.

Present address: Ludwig Inst. for Cancer Research, Karolinska Inst., 17177 Stockholm, Sweden.

Present address: University Hospital Zürich, Inst. for Neuropathology, 8091 Zürich, Switzerland.

^¶ To whom correspondence should be addressed: Forschungszentrum Karlsruhe, Inst. of Toxicology and Genetics, P. O. Box 3640, 76021 Karlsruhe, Germany. Tel.: 49-7247-823302; Fax: 49-7247-823354; E-mail: falk.weih{at}itg.fzk.de.

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