| Nuclear factor (NF)-κB plays a pivotal role in the immune system. My thesis work is to study the mechanism of NF-κB regulation in two critical processes in immune response.; First, we analyzed the regulation of Fas expression by NF-κB. Fas is a key molecule involved in killing of target cells by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and activation induced cell death (AICD) of mature T cells. These apoptosis pathways are dependent on the induction of Fas expression by cytokines such as tumor necrosis factor (TNF)-α, or signals from T cell receptor (TCR) engagement. To investigate the regulatory mechanism of Fas expression, we cloned the promoter region of the murine Fas gene, and located two κB sites that are critical for NF-κB dependent Fas up-regulation induced by TNF-α or phorbol myristate acetate (PMA)/phytohaemagglutinin (PHA). We also tested whether RelA or other NF-κB subunits are critical for Fas regulation in primary T cells, utilizing CD4+ T cells from RelA−/−, p50−/−, and c-Rel−/− mice. Our results showed that expression of Fas and activation-induced cell death were not affected in these T cells. Further analysis suggested that the redundancy of RelA and c-Rel in primary T cells might account for the normal expression of Fas in RelA−/− , p50−/−, and c-Rel−/− T cells.; Second, we studied the function of NF-κB in mature T cell activation, proliferation and apoptosis, utilizing mice deficient of both p50 and c-Rel subunits. CD4+ T cells from these mice have little NF-κB activity after TCR stimulation. Our results showed that NF-κB is required for both survival and proliferation of T cells during activation. This is partly due to NF-κB dependent expression of Bcl-2, Bcl-XL and c-myc. Moreover, once T cells are activated, NF-κB can protect them against passive apoptosis caused by cytokine withdrawal, although this protection pathway is different from IL-2 induced survival pathway. In vivo, p50 −/− c-Rel−/− mice showed impaired superantigen-induced T cell response as well as decreased numbers of effector/memory and regulatory CD4+ T cells. In conclusion, our data demonstrated the essential role of NF-κB in regulating mature T cell function and apoptosis. |
