The Journal of Experimental Medicine
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Published online 25 July 2005 doi:10.1084/jem.20050118
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 3, 405-413
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ARTICLE

 Cellular FLICE-inhibitory protein is required for T cell survival and cycling

Hien Chau1,2, Veronica Wong1,2, Nien-Jung Chen1,2, Huey-Lan Huang1,2, Wen-Jye Lin1,2, Christine Mirtsos1,2, Alisha R. Elford1,2, Madeleine Bonnard3, Andrew Wakeham1,2, Annick Itie You-Ten1,2, Bénédicte Lemmers3, Leonardo Salmena3, Marc Pellegrini1,2, Razq Hakem3, Tak W. Mak1,2, Pamela Ohashi1,2, and Wen-Chen Yeh1,2

1 Campbell Family Institute for Breast Cancer Research, University Health Network
2 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
3 Ontario Cancer Institute, University Health Network, Toronto, Ontario, M5G 2M9, Canada

CORRESPONDENCE Wen-Chen Yeh: wyeh{at}uhnres.utoronto.ca

Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor–induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)–mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag–/– blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP–/–) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8–deficient cells, rcFLIP–/– T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP–/– T cells. We demonstrate an essential role for cFLIP in T cell function.

Abbreviations used: 7-AAD, 7-amino-actinomycin D; cFLIP, cellular FLICE-inhibitory protein; CFSE, carboxyfluorescein diacetate succinimidyl ester; DD, death domain; DED, death effector domain; DR, death receptor; ES, embryonic stem; FADD, Fas-associated DD.

H. Chau and V. Wong contributed equally to this work.


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