Dudley E, Hornung F, Zheng L, Scherer D, Ballard D, Lenardo M
Laboratory of Immunology, NIAID, NIH, Bethesda, MD 20892-1892, USA.
Eur J Immunol. 1999 Mar;29(3):878-86. doi: 10.1002/(SICI)1521-4141(199903)29:03<878::AID-IMMU878>3.0.CO;2-9.
The maintenance of lymphocyte homeostasis by apoptosis is a critical regulatory mechanism in the normal immune system. The transcription factor NF-kappaB has been shown to play a role in protecting cells against death mediated by TNF We show here that NF-kappaB 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-kappaB subunits p50 and p65 confers resistance against Fas-mediated apoptosis. Reciprocally, inhibition of NF-kappaB activation by a soluble peptide inhibitor or a dominant form of the NF-kappaB inhibitor, IkappaB, makes the cells more susceptible to Fas-mediated apoptosis. Furthermore, inhibition of NF-kappaB 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 IkappaB molecule have increased sensitivity to Fas-mediated apoptosis, associated with a down-regulation of NF-kappaB complexes in the nucleus. In addition, blocking TNF, itself a positive regulator of NF-kappaB, with neutralizing antibodies renders the cells more susceptible to anti-Fas-mediated apoptosis. In summary, our results provide compelling evidence that NF-kappaB protects against Fas-mediated death and is likely to be an important regulator of T cell homeostasis and tolerance.
通过凋亡维持淋巴细胞内环境稳定是正常免疫系统中的关键调节机制。转录因子NF-κB已被证明在保护细胞免受TNF介导的死亡中发挥作用。我们在此表明，NF-κB在调节Fas/APO-1/CD95介导的死亡中也起作用，这是外周T细胞死亡的主要途径。用NF-κB亚基p50和p65转染Jurkat细胞可赋予其对Fas介导的凋亡的抗性。相反，可溶性肽抑制剂或NF-κB抑制剂IkappaB的显性形式对NF-κB激活的抑制使细胞更易受Fas介导的凋亡影响。此外，可溶性肽抑制剂对NF-κB激活的抑制使T细胞杂交瘤更易受TCR介导的凋亡影响。相应地，p50和p65的转染提供了对TCR介导的凋亡的显著保护。对原代T细胞中Fas介导的死亡的研究证实了这些观察结果。来自转染显性IkappaB分子的小鼠的伴刀豆球蛋白A激活的循环T细胞母细胞对Fas介导的凋亡的敏感性增加，这与细胞核中NF-κB复合物的下调有关。此外，用中和抗体阻断TNF（其本身是NF-κB的正调节因子）会使细胞更易受抗Fas介导的凋亡影响。总之，我们的结果提供了令人信服的证据，即NF-κB可保护细胞免受Fas介导的死亡，并且可能是T细胞内环境稳定和耐受性的重要调节因子。
