title: NF-kappa B controls cell fate specification, survival, and molecular differentiation of immunoregulatory natural T lymphocytes.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Aleksandar K
authors.initials: AK
authors.lastname: Stanic
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.forename: Jang-June
authors.initials: JJ
authors.lastname: Park
authors.forename: Naoto
authors.initials: N
authors.lastname: Matsuki
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boothby
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
mesh_terms: D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D000954:Antigens, Surface; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D020672:I-kappa B Proteins / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D055651:NK Cell Lectin-Like Receptor Subfamily B; D014176:Protein Biosynthesis; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D000941:Antigens; D000954:Antigens, Surface; C494812:Bcl2l1 protein, mouse; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; D037181:Lectins, C-Type; D016328:NF-kappa B; D055651:NK Cell Lectin-Like Receptor Subfamily B; C000606205:Nfkbia protein, mouse; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha