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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.

Original publication

DOI

10.4049/jimmunol.172.4.2265

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

02/2004

Volume

172

Pages

2265 - 2273

Addresses

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Keywords

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