NF-kappa B RelA (p65) is essential for TNF-alpha-induced Fas expression but dispensable for both TCR-induced expression and activation-induced cell death

The Fas death receptor plays a key role in the killing of target cells by N K cells and CTLs and in activation-induced cell death of mature T lymphocyt es. These cytotoxic pathways are dependent on induction of Fas expression b y cytokines such as TNF-a and IFN-gamma or by signals generated after TCR e ngagement. Although much of our knowledge of the Fas death pathway has been generated from murine studies, little is known about regulatory mechanisms important for murine Fas expression. To this end, we have molecularly clon ed a region of the murine Fas promoter that is responsible for mediating TN F-alpha and PMA/PHA-induced expression. We demonstrate here that induction of Fas expression by both stimuli is critically dependent on two sites that associate with RelA-containing NF-kappaB complexes. To determine whether R elA and/or other NF-kappaB subunits are also important for regulating Fas e xpression in primary T cells, we used CD4 T cells from RelA(-/-), c-Rel(-/- ), and p50(-/-) mice. Although proliferative responses were significantly i mpaired, expression of Fas and activation-induced cell death was unaffected in T cells obtained from these different mice. Importantly, we show that u nlike fibroblasts, which consist primarily of RelA-containing NF-kappaB com plexes, T cells have high levels of both RelA and c-Rel complexes, suggesti ng that Fas expression in T cells may be dependent on redundant functions o f these NF-kappaB subunits.