Antiapoptotic function of NF-kappaB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL

Cell Death Differ. 2003 Sep;10(9):1032-44. doi: 10.1038/sj.cdd.4401257.


Inducible protection from apoptosis in vivo controls the size of cell populations. An important question in this respect is how differentiation affects mechanisms of apoptosis regulation. Among mature T lymphocytes, the NF-kappaB/Rel transcription factors are coupled to receptors that control cell population sizes by concurrently regulating survival and multiplication. In the present study, we used a transgenic inhibitor of NF-kappaB/Rel signaling to investigate the role of this pathway in proliferation and death of mature T cells in vivo. The results indicate that NF-kappaB integrates two critical yet distinct molecular pathways preventing apoptosis affected by the death receptor Fas, coordinately regulating levels of FLIP and Bcl-x(L) in primary T cells. Surprisingly, NF-kappaB blockade preferentially impacted naive as compared to memory T cells. The Fas/FasL pathway was linked to these findings by evidence that the abnormalities imposed by NF-kappaB inhibition were ameliorated by Fas deficiency, particularly for the CD4(+) lineage. Moreover, levels of an inhibitor of Fas-mediated apoptosis, c-FLIP, were diminished in cells expressing the transgenic inhibitor. NF-kappaB was also linked to T cell survival in vivo by mediating induction of Bcl-x(L): restoration of Bcl-x(L) levels reversed the preferential deficit of naive T cells, differentially impacting the CD4 and CD8 subsets. These results show that promoting survival and effective multiplication are central roles for NF-kappaB in T lymphoid homeostasis in vivo, but this effect and its underlying mechanisms are influenced by the developmental state of the lymphocyte.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / physiology
  • Cell Cycle
  • Cell Differentiation
  • Cytoprotection
  • Fas Ligand Protein
  • I-kappa B Proteins / genetics
  • Intracellular Signaling Peptides and Proteins*
  • Lymphocyte Activation
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Transgenic
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Signal Transduction
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • bcl-X Protein
  • fas Receptor / physiology


  • Bcl2l1 protein, mouse
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Cflar protein, mouse
  • Fas Ligand Protein
  • Fasl protein, mouse
  • I-kappa B Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • fas Receptor
  • NF-KappaB Inhibitor alpha