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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Biological Transport
  • Concanavalin A / metabolism
  • Concanavalin A / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • I-kappa B Proteins
  • Jurkat Cells
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • Nuclear Localization Signals
  • Peptides / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / metabolism*
  • Transcription Factor RelA
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism*


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Nuclear Localization Signals
  • Peptides
  • Receptors, Antigen, T-Cell
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Concanavalin A