Cutting edge: FADD is not required for antigen receptor-mediated NF-kappaB activation.
Recently, it has been demonstrated that stimulated T cells bearing defects in caspase-8 fail to promote nuclear shuttling of NF-kappaB complexes. Such cells display strikingly similar proliferative and survival defects as T cells lacking Fas-associated death domain protein (FADD) function. We characterized NF-kappaB signaling in T cells bearing a dominant-negative FADD transgene (FADDdd). Whereas FADDdd T cells displayed proliferative defects following activation, these were not a consequence of aberrant NF-kappaB signaling, as measured by IKK/IkappaB phosphorylation and IkappaB degradation. There were no appreciable defects in nuclear translocation of p65/Rel using ImageStream, a flow-based imaging cytometer. Pretreatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a potent caspase inhibitor, also failed to impede canonical NF-kappaB signaling. Secretion of IL-2 and up-regulation of various activation markers occurred normally. Thus, FADD does not play an essential role in NF-kappaB activation, suggesting an alternative route by which this adaptor promotes the clonal expansion of T cells.
Arechiga
Adrian F
AF
Center for Immunology and Department of Molecular Biology & Biochemistry, University of California, Irvine. CA 92697, USA.
Bell
Bryan D
BD
Solomon
Jennifer C
JC
Chu
Isaac H
IH
Dubois
Claire L
CL
Hall
Brian E
BE
George
Thaddeus C
TC
Coder
David M
DM
Walsh
Craig M
CM
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D011948:Receptors, Antigen, T-Cell; D051996:Transcription Factor RelA