Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12827-32. doi: 10.1073/pnas.1105774108. Epub 2011 Jul 18.
Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-κB-inducing kinase (NIK), a central component of the noncanonical NF-κB signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-κB. Our findings suggest that the noncanonical NF-κB pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.
滤泡辅助 T（Tfh）细胞在介导体液免疫反应中起核心作用。Tfh 细胞的产生既依赖于 T 细胞内在因素，也依赖于 B 细胞的支持功能，但潜在的分子机制尚不完全清楚。在这里，我们表明，核因子 κB 诱导激酶（NIK），非经典 NF-κB 信号通路的核心组成部分，是 Tfh 细胞发育所必需的。与其他已知的 Tfh 调节剂不同，NIK 通过控制 B 细胞的支持功能起作用。NIK 和其上游 BAFF 受体调节 B 细胞表达诱导共刺激配体（ICOSL），这是生成 Tfh 细胞所必需的分子。一致地，向 NIK 缺陷型小鼠注射重组 ICOSL 蛋白在很大程度上挽救了它们在 Tfh 细胞发育中的缺陷。我们提供了生化和遗传证据，表明 ICOSL 基因是非经典 NF-κB 的一个特定靶标。我们的发现表明，非经典 NF-κB 途径通过在 B 细胞中介导 ICOSL 基因表达来调节 Tfh 细胞的发育。
