A non-apoptotic FADD/caspase-8 dependent mechanism essential for T cell clonal expansion (87.48)

• Published in: The Journal of immunology (1950) Vol. 178; no. 1_Supplement; p. S137
• Main Authors: Walsh, Craig Michael, Leverrier, Sabrina, Bell, Bryan D., Arechiga, Adrian F., Weist, Brian M.
• Format: Journal Article
• Language: English
• Published: 01.04.2007
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.Supp.87.48

Abstract FADD constitutes an essential component of TNF receptor-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. Using mice expressing a T cell specific transgene encoding the death domain of FADD (FADDdd), we have found that FADD participates in T cell clonal expansion. Based on BrdU uptake assays, we have found that FADD signaling is required for transition between the late G1 and S-phase of cell cycle. The defective progression through cycle is marked by a defect in cyclin E expression and CDK2 activation. We have also identified a defect in the maintenance of S6K1 activity and ribosomal S6 phosphorylation, two essential intermediaries of proliferative signaling in T cells. We have found that caspase-8 is essential in this FADD dependent process, suggesting that FADD promotes the assembly of a non-apoptotic caspase-8 complex that serves to relieve inhibition of cell cycle progression during the G1/S transition. In line with this hypothesis, we have found that caspase-8 activity is induced in T cells in a cell-cycle dependent manner in normal T cells. The potential that this signaling axis may modulate autophagy is presently under investigation. Since TNF receptor family members play key roles in regulating adaptive immunity, these results suggest that FADD and caspase-8 serve multiple functions to maintain immune homeostasis.