Elewaut Dirk, Shaikh Raziya B, Hammond Kirsten J L, De Winter Hilde, Leishman Andrew J, Sidobre Stephane, Turovskaya Olga, Prigozy Theodore I, Ma Lisa, Banks Theresa A, Lo David, Ware Carl F, Cheroutre Hilde, Kronenberg Mitchell
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121, USA.
J Exp Med. 2003 Jun 16;197(12):1623-33. doi: 10.1084/jem.20030141.
A defect in RelB, a member of the Rel/nuclear factor (NF)-kappa B family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-kappa B-inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/- x aly/+ compound heterozygous mice. After stimulation with alpha-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/- or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell.
RelB是Rel/核因子（NF）-κB转录因子家族的成员之一，其缺陷会影响抗原呈递细胞和淋巴器官的形成，但其在T淋巴细胞分化中的作用尚未得到充分阐明。在此，我们表明小鼠中RelB缺陷会导致自然杀伤T（NKT）细胞选择性减少。RelB必须在可抗辐射的宿主细胞中表达，该细胞可以是CD1d阴性，这表明表达RelB的细胞并不直接参与CD1d依赖性NKT细胞的阳性选择。与RelB缺陷小鼠一样，携带NF-κB诱导激酶（NIK）突变的aly/aly小鼠的NKT细胞数量也减少。对aly/aly小鼠胸腺中NKT细胞上NK1.1和CD44表达的分析揭示了发育过程中的晚期阻滞。在体外，我们表明在表面受体触发时，NIK是RelB激活所必需的。通过分析RelB+/-×aly/+复合杂合小鼠，在体内进一步证实了NIK与RelB之间的这种联系。用α-半乳糖神经酰胺（一种NKT细胞识别的抗原）刺激后，与RelB+/-或aly/+小鼠相比，这些复合杂合子的反应减弱。这些数据说明了造血细胞和非造血细胞类型在NKT细胞发育过程中的复杂相互作用，并且证明了NKT细胞对由胸腺基质细胞中NIK激活RelB介导的信号通路的独特需求。
