Sivakumar Vallabhapurapu, Hammond Kirsten J L, Howells Norma, Pfeffer Klaus, Weih Falk
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany.
J Exp Med. 2003 Jun 16;197(12):1613-21. doi: 10.1084/jem.20022234.
Natural killer T (NKT) cells have been implicated in diverse immune responses ranging from suppression of autoimmunity to tumor rejection. Thymus-dependent NKT cells are positively selected by the major histocompatibility complex class I-like molecule CD1d, but the molecular events downstream of CD1d are still poorly understood. Here, we show that distinct members of the Rel/nuclear factor (NF)-kappa B family of transcription factors were required in both hematopoietic and nonhematopoietic cells for normal development of thymic NKT cells. Activation of NF-kappa B via the classical I kappa B alpha-regulated pathway was required in a cell autonomous manner for the transition of NK-1.1-negative precursors that express the TCR V alpha 14-J alpha 18 chain to mature NK-1.1-positive NKT cells. The Rel/NF-kappa B family member RelB, on the other hand, had to be expressed in radiation resistant thymic stromal cells for the generation of early NK-1.1-negative NKT precursors. Moreover, NF-kappa B-inducing kinase (NIK) was required for both constitutive thymic DNA binding of RelB and the specific induction of RelB complexes in vitro. Thus, distinct Rel/NF-kappa B family members in hematopoietic and nonhematopoietic cells regulate NKT cell development with a unique requirement for NIK-mediated activation of RelB in thymic stroma.
自然杀伤T（NKT）细胞参与了从自身免疫抑制到肿瘤排斥等多种免疫反应。胸腺依赖性NKT细胞由主要组织相容性复合体I类样分子CD1d阳性选择，但CD1d下游的分子事件仍知之甚少。在此，我们表明，转录因子Rel/核因子（NF）-κB家族的不同成员在造血细胞和非造血细胞中都是胸腺NKT细胞正常发育所必需的。通过经典的IκBα调节途径激活NF-κB以细胞自主方式是表达TCR Vα14-Jα18链的NK-1.1阴性前体向成熟的NK-1.1阳性NKT细胞转变所必需的。另一方面，Rel/NF-κB家族成员RelB必须在抗辐射的胸腺基质细胞中表达，以产生早期NK-1.1阴性NKT前体。此外，NF-κB诱导激酶（NIK）对于RelB的组成型胸腺DNA结合和体外RelB复合物的特异性诱导都是必需的。因此，造血细胞和非造血细胞中不同的Rel/NF-κB家族成员调节NKT细胞发育，对胸腺基质中NIK介导的RelB激活有独特要求。
