Cellular FLICE-inhibitory protein is required for T cell survival and cycling.
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.
Chau
Hien
H
Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada.
Wong
Veronica
V
Chen
Nien-Jung
NJ
Huang
Huey-Lan
HL
Lin
Wen-Jye
WJ
Mirtsos
Christine
C
Elford
Alisha R
AR
Bonnard
Madeleine
M
Wakeham
Andrew
A
You-Ten
Annick Itie
AI
Lemmers
Bénédicte
B
Salmena
Leonardo
L
Pellegrini
Marc
M
Hakem
Razq
R
Mak
Tak W
TW
Ohashi
Pamela
P
Yeh
Wen-Chen
WC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens; D017252:CD3 Complex; C506387:Cflar protein, mouse; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases