Stanic Aleksandar K, Bezbradica Jelena S, Park Jang-June, Matsuki Naoto, Mora Ana L, Van Kaer Luc, Boothby Mark R, Joyce Sebastian
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Immunol. 2004 Feb 15;172(4):2265-73. 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.
免疫调节性自然杀伤T（iNKT）淋巴细胞的个体发生、稳态和功能缺陷是包括自身免疫在内的各种炎症性免疫疾病的基础。控制iNKT细胞命运决定和分子分化的信号事件仅得到部分理解。在此，我们证明iNKT细胞内的这些过程需要经典的核因子κB（NF-κB）信号传导。NF-κB信号传导的抑制在未成熟阶段阻断iNKT细胞的个体发生，并揭示了一个明显的、新的前体，其中发生阴性选择。最重要的是，这种阻断是由于缺乏存活信号所致，因为Bcl-xL的过表达可挽救iNKT细胞的个体发生。未成熟iNKT细胞前体的成熟诱导Bcl-2表达，在缺乏NF-κB信号传导时该表达存在缺陷。Bcl-xL的过表达也挽救了这种成熟诱导的Bcl-2表达。因此，由NF-κB传递的抗凋亡信号严格控制iNKT细胞的命运决定和分子分化，从而揭示了此类信号在免疫系统中的新作用。
