Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China.
Nat Immunol. 2018 Nov;19(11):1224-1235. doi: 10.1038/s41590-018-0206-z. Epub 2018 Sep 24.
Dendritic cells (DCs) play an integral role in regulating mucosal immunity and homeostasis, but the signaling network mediating this function of DCs is poorly defined. We identified the noncanonical NF-κB-inducing kinase (NIK) as a crucial mediator of mucosal DC function. DC-specific NIK deletion impaired intestinal immunoglobulin A (IgA) secretion and microbiota homeostasis, rendering mice sensitive to an intestinal pathogen, Citrobacter rodentium. DC-specific NIK was required for expression of the IgA transporter polymeric immunoglobulin receptor (pIgR) in intestinal epithelial cells, which in turn relied on the cytokine IL-17 produced by T17 cells and innate lymphoid cells (ILCs). NIK-activated noncanonical NF-κB induced expression of IL-23 in DCs, contributing to the maintenance of T17 cells and type 3 ILCs. Consistent with the dual functions of IL-23 and IL-17 in mucosal immunity and inflammation, NIK deficiency also ameliorated colitis induction. Thus, our data suggest a pivotal role for the NIK signaling axis in regulating DC functions in intestinal immunity and homeostasis.
树突状细胞（DCs）在调节黏膜免疫和稳态中发挥着重要作用，但介导 DC 这一功能的信号网络尚未完全明确。我们发现非典型 NF-κB 诱导激酶（NIK）是黏膜 DC 功能的关键介质。DC 特异性 NIK 缺失会损害肠道免疫球蛋白 A（IgA）分泌和微生物群落稳态，使小鼠易感染肠道病原体柠檬酸杆菌。DC 特异性 NIK 对于肠道上皮细胞中 IgA 转运体多聚免疫球蛋白受体（pIgR）的表达是必需的，而后者又依赖于 T17 细胞和固有淋巴细胞（ILCs）产生的细胞因子 IL-17。NIK 激活的非典型 NF-κB 诱导 DC 中 IL-23 的表达，有助于 T17 细胞和 3 型 ILC 的维持。与 IL-23 和 IL-17 在黏膜免疫和炎症中的双重功能一致，NIK 缺失也改善了结肠炎的诱导。因此，我们的数据表明 NIK 信号轴在调节肠道免疫和稳态中的 DC 功能方面发挥着关键作用。
