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

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Abstract
The maintenance of lymphocyte homeostasis by apoptosis is a critical regulatory mechanism in the normal immune system. The transcription factor NF-κB has been shown to play a role in protecting cells against death mediated by TNF. We show here that NF-κB also has a role in regulating Fas / APO-1 / CD95-mediated death, a major pathway of peripheral T cell death. Transfection of Jurkat cells with the NF-κB subunits p50 and p65 confers resistance against Fas-mediated apoptosis. Reciprocally, inhibition of NF-κB activation by a soluble peptide inhibitor or a dominant form of the NF-κB inhibitor, IκB, makes the cells more susceptible to Fas-mediated apoptosis. Furthermore, inhibition of NF-κB activation by a soluble peptide inhibitor rendered a T cell hybridoma more susceptible to TCR-mediated apoptosis. Correspondingly, transfection of p50 and p65 provided considerable protection from TCR-mediated apoptosis. These observations were corroborated by studies on Fas-mediated death in primary T cells. Concanavalin A-activated cycling T cell blasts from mice that are transgenic for the dominant IκB molecule have increased sensitivity to Fas-mediated apoptosis, associated with a down-regulation of NF-κB complexes in the nucleus. In addition, blocking TNF, itself a positive regulator of NF-κB, with neutralizing antibodies renders the cells more susceptible to anti-Fas-mediated apoptosis. In summary, our results provide compelling evidence that NF-κB protects against Fas-mediated death and is likely to be an important regulator of T cell homeostasis and tolerance.