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

Mora AL, Corn RA, Stanic AK, Goenka S, Aronica M, Stanley S, Ballard DW, Joyce S, Boothby M
Cell Death Differ. 2003 10 (9): 1032-44

PMID: 12934078 · 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.

MeSH Terms (21)

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

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