LYMPHOCYTE SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B REGULATORS

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Regulation of genes for several lymphokines depend on a 10 bp DNA sequence termed kappaB. In addition, it has recently been shown that expression of the factor RelA that binds to this sequence is important in protecting cells from programmed cell death. We have been investigating its role in these processes using several approaches. First, we have been examining programmed cell death in lymphocytes of mice that are impaired in their activation of the kappaB sequence due to a dominant interfering I-kappaB regulatory protein. Preliminary results suggest that the T-cells from these mice may be more susceptible to death induced by tumor necrosis factor, and that this is particularly striking in CD8+ T-cells. Separately, we have found data that suggest that production of IL-4, a lymphokine involved in defense against extracellular parasites may be impaired. These experiments are currently being repeated. If verified, corroboration will come from examining an immune system lacking RelA that is reconstituted in mice that are unable to make their own T-cells. Related to these experiments is a recent initiative to characterize a RelA binding site in the promoter of the CCR5 chemokine receptor. This receptor has been shown to serve as an obligatory co-receptor for the infection of cells with the macrophage-tropic strains of HIV. This co-receptor may be strongly influenced by CD28 stimulation and this could be due to the effect of NF-kappaB on the CCR5 promoter. A further series of experiments designed to investigate the association of death and apoptosis has just been started. There have been suggestions in the literature that the death receptor Fas can activate NF-kappaB, but the physiologic significance of this is unclear. We hypothesize that low level activation of the Fas molecule can, in turn, activate NF-kappaB, promoting cell survival. Using sensitive reporter constructs, we are now investigating the extent to which the hypothesized activation occurs. If positive results are obtained, we will then investigate the potential for this signal to provide protection against programmed cell death induced by other mechanisms.