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

Hien Chau, Veronica Wong, Nien Jung Chen, Huey Lan Huang, Wen Jye Lin, Christine Mirtsos, Alisha R. Elford, Madeleine Bonnard, Andrew Wakeham, Annick Itie You-Ten, Bénédicte Lemmers, Leonardo Salmena, Marc Pellegrini, Razq Hakem, Tak W. Mak, Pamela Ohashi, Wen Chen Yeh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

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. JEM

Original languageEnglish
Pages (from-to)405-413
Number of pages9
JournalJournal of Experimental Medicine
Volume202
Issue number3
DOIs
StatePublished - 1 Aug 2005

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