A role for FADD in T cell activation and development.
FADD is a cytoplasmic adapter molecule that links the family of death receptors to the activation of caspases during apoptosis. We have produced transgenic mice expressing a dominantly interfering mutant of FADD, lacking the caspase-dimerizing death effector domain, as well as mice overexpressing the poxvirus serpin, CrmA, an inhibitor of caspases downstream of FADD. While thymocytes from either line of mice were completely protected from CD95-dependent cytotoxicity, neither transgene afforded protection from apoptosis induced during thymocyte selection and neither led to the lymphoproliferative disorders associated with deficiencies in CD95. However, in FADD dominant negative (FADDdd) mice, early thymocyte development was retarded and peripheral lymphocyte pools were devoid of normal populations of T cells. We show that thymocytes and peripheral T cells from FADDdd display signaling anomalies, implying that FADD plays a previously uncharacterized role in T cell development and activation.
Walsh
C M
CM
Department of Biology and the Cancer Center, The University of California, San Diego, La Jolla 92093-0687, USA.
Wen
B G
BG
Chinnaiyan
A M
AM
O'Rourke
K
K
Dixit
V M
VM
Hedrick
S M
SM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008206:Lymphatic Diseases / Q000209:etiology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011212:Poxviridae / Q000235:genetics; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014764:Viral Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D003546:Cysteine Endopeptidases