Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Mucosal Immunol. 2018 Jan;11(1):82-96. doi: 10.1038/mi.2017.48. Epub 2017 Jun 15.
Intranasal inoculation with influenza hemagglutinin subunit with polyinosine-polycytidylic (polyI:C), a synthetic analog for double-stranded RNA, enhances production of vaccine-specific immunoglobulin (Ig) A, which is superior to IgG in prophylactic immunity. The mechanism whereby polyI:C skews to IgA production in the nasal-associated lymph tissue (NALT) was investigated in mouse models. Nasally instilled polyI:C was endocytosed into CD103 dendritic cells (DCs) and induced T-cell activation, including interferon (IFN)-γ production. According to knockout mouse studies, polyI:C activated the Toll-like receptor 3 signal via the adapter TICAM-1 (also called TRIF), that mainly caused T-cell-dependent IgA production. Nasal CD103 DCs activated transforming growth factor-β signaling and activation-induced cytidine deaminase upon polyI:C stimulation. IgA rather than IgG production was impaired in Batf3 mice, where CD103 DCs are defective. Genomic recombination occurred in IgA-producing cells in association with polyI:C-stimulated DCs and nasal microenvironment. PolyI:C induced B-cell-activating factor expression and weakly triggered T-cell-independent IgA production. PolyI:C simultaneously activated mitochondrial antiviral signaling and then type I IFN receptor pathways, which only minimally participated in IgA production. Taken together, CD103 DCs in NALT are indispensable for the adjuvant activity of polyI:C in enhancing vaccine-specific IgA induction and protective immunity against influenza viruses.
鼻腔接种流感血凝素亚单位与聚肌苷酸-聚胞苷酸（polyI:C），一种双链 RNA 的合成类似物，可增强疫苗特异性免疫球蛋白（Ig）A 的产生，其在预防免疫中优于 IgG。本研究旨在探讨 polyI:C 在鼻相关淋巴组织（NALT）偏向 IgA 产生的机制。滴鼻给予的 polyI:C 被 CD103 树突状细胞（DCs）内吞，并诱导 T 细胞活化，包括干扰素（IFN）-γ的产生。根据敲除小鼠研究，polyI:C 通过衔接子 TICAM-1（也称为 TRIF）激活 Toll 样受体 3 信号，主要引起 T 细胞依赖性 IgA 产生。鼻 CD103 DCs 在 polyI:C 刺激下激活转化生长因子-β信号和激活诱导胞苷脱氨酶。Batf3 小鼠（CD103 DC 缺陷）中，polyI:C 诱导的 IgA 而非 IgG 产生受损。与 polyI:C 刺激的 DC 和鼻微环境相关，IgA 产生细胞发生了基因组重组。polyI:C 诱导 B 细胞激活因子的表达，并弱触发 T 细胞非依赖性 IgA 产生。polyI:C 同时激活线粒体抗病毒信号，然后是 I 型 IFN 受体途径，它们仅轻微参与 IgA 产生。综上所述，NALT 中的 CD103 DC 对于 polyI:C 增强疫苗特异性 IgA 诱导和抗流感病毒保护性免疫的佐剂活性是必不可少的。
