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

• Published in: The Journal of immunology (1950) 2004-02, Vol.172 (4), p.2265-2273
• Main Authors: Stanic, Aleksandar K, Bezbradica, Jelena S, Park, Jang-June, Matsuki, Naoto, Mora, Ana L, Van Kaer, Luc, Boothby, Mark R, Joyce, Sebastian
• Format: Article
• Language: English
• Subjects: Animals; Antigens - biosynthesis; Antigens, Surface; Apoptosis - genetics; Apoptosis - immunology; Bcl-x protein; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Division - genetics; Cell Division - immunology; Cell Lineage - genetics; Cell Lineage - immunology; Cell Survival - genetics; Cell Survival - immunology; Growth Inhibitors - genetics; Growth Inhibitors - physiology; I-kappa B Proteins - physiology; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lectins, C-Type; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - physiology; NF-KappaB Inhibitor alpha; NK Cell Lectin-Like Receptor Subfamily B; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Signal Transduction - genetics; Signal Transduction - immunology; Stem Cells - cytology; Stem Cells - immunology; Stem Cells - metabolism; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 0022-1767; 1550-6606
• 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.