NF-chi B regulates Fas/APO-1/CD95- and TCR-mediated apoptosis of T lymphocytes

The maintenance of lymphocyte homeostasis by apoptosis is a critical regula tory mechanism in the normal immune system. The transcription factor NF-kap pa B has been shown to play a role in protecting cells against death mediat ed by TNF. We show here that NF-kappa B also has a role in regulating Fas/A PO-1/CD95-mediated death, a major pathway of peripheral T cell death. Trans fection of Jurkat cells with the NF-kappa B subunits p50 and p65 confers re sistance against Fas-mediated apoptosis. Reciprocally, inhibition of NF-kap pa B activation by a soluble peptide inhibitor or a dominant form of the NF -kappa B inhibitor, I kappa B, makes the cells more susceptible to Fas-medi ated apoptosis. Furthermore, inhibition of NF-kappa B activation by a solub le peptide inhibitor rendered a T cell hybridoma more susceptible to TCR-me diated apoptosis. Correspondingly, transfection of p50 and p65 provided con siderable protection from TCR-mediated apoptosis. These observations were c orroborated by studies on Fas-mediated death in primary T cells. Concanaval in A-activated cycling T cell blasts from mice that are transgenic for the dominant I kappa B molecule have increased sensitivity to Fas-mediated apop tosis, associated with a down-regulation of NF-kappa B complexes in the nuc leus. In addition, blocking TNF, itself a positive regulator of NF-kappa B, with neutralizing antibodies renders the cells more susceptible to anti-Fa s-mediated apoptosis. In summary, our results provide compelling evidence t hat NF-kappa B protects against Fas-mediated death and is likely to be an i mportant regulator of T cell homeostasis and tolerance.