NF-kappa B controls cell fate specification, survival, and molecular differentiation of immunoregulatory natural T lymphocytes.

Stanic AK, Bezbradica JS, Park JJ, Matsuki N, Mora AL, Van Kaer L, Boothby MR, Joyce S
J Immunol. 2004 172 (4): 2265-73

PMID: 14764695 · DOI:10.4049/jimmunol.172.4.2265

Ontogenetic, homeostatic, and functional deficiencies within immunoregulatory natural T (iNKT) lymphocytes underlie various inflammatory immune disorders including autoimmunity. Signaling events that control cell fate specification and molecular differentiation of iNKT cells are only partly understood. Here we demonstrate that these processes within iNKT cells require classical NF-kappaB signaling. Inhibition of NF-kappaB signaling blocks iNKT cell ontogeny at an immature stage and reveals an apparent, novel precursor in which negative selection occurs. Most importantly, this block occurs due to a lack of survival signals, as Bcl-x(L) overexpression rescues iNKT cell ontogeny. Maturation of immature iNKT cell precursors induces Bcl-2 expression, which is defective in the absence of NF-kappaB signaling. Bcl-x(L) overexpression also rescues this maturation-induced Bcl-2 expression. Thus, antiapoptotic signals relayed by NF-kappaB critically control cell fate specification and molecular differentiation of iNKT cells and, hence, reveal a novel role for such signals within the immune system.

MeSH Terms (26)

Animals Antigens Antigens, Surface Apoptosis bcl-X Protein Cell Differentiation Cell Division Cell Lineage Cell Survival Growth Inhibitors I-kappa B Proteins Killer Cells, Natural Lectins, C-Type Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic NF-kappa B NF-KappaB Inhibitor alpha NK Cell Lectin-Like Receptor Subfamily B Protein Biosynthesis Proteins Proto-Oncogene Proteins c-bcl-2 Signal Transduction Stem Cells T-Lymphocyte Subsets

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