NON-APOPTOTIC INDUCTION OF CASPASE-8 IN T-CELLS DEPENDS ON FADD AND CELL CYCLE PROGRESSION (87.1)

• Published in: The Journal of immunology (1950) Vol. 178; no. 1_Supplement; p. S127
• Main Authors: Leverrier, Sabrina, Weist, Brian M, Walsh, Craig M
• Format: Journal Article
• Language: English
• Published: 01.04.2007
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.Supp.87.1

Abstract Upon triggering of apoptosis by tumor necrosis factor (TNF) receptor family member engagement, FADD (Fas-Associated Death Domain-containing protein) acts as an adaptor protein by recruiting caspase-8 and promoting its autocatalytic activation. Surprisingly, it was found that FADD and caspase-8 are also critical for T lymphocytes proliferation. Indeed, T cell specific overexpression of a FADD dominant-negative mutant (FADDdd) or conditional deletion of caspase-8 or FADD in T cells leads to profound defects in proliferation. While it is known that FADD transmits an apoptotic signal by recruiting caspase-8 within the cytoplasm, it is unclear how FADD and caspase-8 promote T cell proliferation. Since it has been shown that both proteins can localize within the nucleus, we investigated caspase-8 catalytic activity in the nucleus of proliferating T cells and detected an increasing level of caspase-8 activity upon stimulation with anti-CD3 and anti-CD28. Using FADDdd T cells, we determined that this nuclear catalytic activity was dependent on normal FADD function. Blocking cell cycle progression at different stages also drastically reduced caspase-8 activation in non-apoptotic T cells, whereas inhibiting TNF receptor activation did not appreciably diminish caspase-8 activity. We are currently attempting to identify caspase-8 nuclear substrates involved in T-cell proliferation. Taken together, our results suggest that specific subcellular compartmentalization is associated with a distinct magnitude in caspase-8 activity, possibly leading to new substrate selectivity during cell cycle progression. These findings may explain how two apoptotic regulatory proteins, FADD and caspase-8, alternatively promote cell death or proliferation in T cells.