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Molecular and Cellular Biology, August 2002, p. 5419-5433, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5419-5433.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

Susanne M. A. Lens,{dagger},1 Takao Kataoka,1,2 Karen A. Fortner,3 Antoine Tinel,1 Isabel Ferrero,4 Robson H. MacDonald,4 Michel Hahne,1 Friedrich Beermann,5 Antoine Attinger,4 Hans-Acha Orbea,1,4 Ralph C. Budd,3 and Jürg Tschopp1*

Department of Biochemistry, University of Lausanne,1 Ludwig Institute for Immunology, Lausanne Branch,,4 ISREC, Epalinges, Switzerland,5 Department of Bioengineering, Tokyo Institute of Technology, Yokohama, Japan,2 Immunobiology Program, University of Vermont College of Medicine, Burlington, Vermont3

Received 5 April 2002/ Accepted 15 April 2002

The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4- CD8- T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

* Corresponding author. Mailing address: Institute of Biochemistry, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. Phone: 41-21 692 5738. Fax: 41-21 692 5705. E-mail: jurg.tschopp{at}ib.unil.ch.

{dagger} Present address: Department of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Molecular and Cellular Biology, August 2002, p. 5419-5433, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5419-5433.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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