Journal
JOURNAL OF IMMUNOLOGY
Volume 172, Issue 4, Pages 2265-2273Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.172.4.2265
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Funding
- NHLBI NIH HHS [HL61752, HL68744] Funding Source: Medline
- NIAID NIH HHS [AI42284, AI50953, AI49460] Funding Source: Medline
- NINDS NIH HHS [NS44044] Funding Source: Medline
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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 occur's 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.
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