Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Front Immunol. 2018 Dec 18;9:2986. doi: 10.3389/fimmu.2018.02986. eCollection 2018.
Intranasal chitosan-formulated DNA vaccination promotes IgA secretion in the intestine. However, the mechanism whereby chitosan-DNA skews IgA class switch recombination (CSR) of B cells in the Gut-associated lymph tissue (GALT) is not fully resolved. In this study, we investigated the effects of nasally administered chitosan-DNA (pcDNA3.1-VP1 plasmid encoding VP1 capsid protein of Coxsackievirus B3) on IgA production, DC activation and Tfh/Th17 response in the intestine. Compared to DNA immunization, intranasal chitosan-DNA vaccination induced antigen-specific IgA production in feces, a pronounced switching of antigen-specific IgA plasmablast B cells in the mesenteric lymph nodes (MLNs) and an enhanced expression of post-recombination Iα-CH transcripts/IgA germline transcript (αGT) as well as activation-induced cytidine deaminase (AID) in MLN B cells. MLN Tfh frequency was markedly enhanced by chitosan-DNA, and was associated with VP1-specific IgA titer. 24 h after immunization, intranasal chitosan-DNA induced a recruitment of CD103DCs into the MLN that paralleled a selective loss of CD103DCs in the lamina propria (LP). activated MLN-derived CD103DCs produced high levels of IL-6 and BAFF in response to chitosan-DNA, which up-regulated transmembrane activator and CAML interactor (TACI) expression on MLN B cells. Upon co-culture with IgMB in the presence of chitosan-DNA, MLN CD103DCs induced IgA production in a T-dependent manner; and this IgA-promoting effect of CD103DC was blocked by targeting TACI and, to a lower extent, by blocking IL-6. MLN CD103DCs displayed an enhanced capacity to induce an enhanced CD4Th17 response and , and IL-17A deficient mice had a pronounced reduction of specific intestinal IgA following immunization. Taken together, mesenteric CD103DCs are indispensable for the adjuvant activity of chitosan in enhancing DNA vaccine-specific IgA switching in gut through activating BAFF-TACI and IL-6-IL-6R signaling, and through inducing Th17/Tfh differentiation in the MLN.
鼻腔内壳聚糖配方 DNA 疫苗可促进肠道中的 IgA 分泌。然而，壳聚糖-DNA 使肠道相关淋巴组织 (GALT) 中的 B 细胞发生 IgA 类别转换重组 (CSR) 的机制尚未完全解决。在这项研究中，我们研究了鼻腔给予壳聚糖-DNA（pcDNA3.1-VP1 质粒编码柯萨奇病毒 B3 的 VP1 衣壳蛋白）对肠道中 IgA 产生、DC 激活和 Tfh/Th17 反应的影响。与 DNA 免疫相比，鼻腔内壳聚糖-DNA 疫苗可诱导粪便中抗原特异性 IgA 的产生，在肠系膜淋巴结 (MLN) 中明显转换抗原特异性 IgA 浆母细胞，并增强 MLN B 细胞中重组后 Iα-CH 转录物/IgA 种系转录物 (αGT) 和激活诱导胞苷脱氨酶 (AID) 的表达。壳聚糖-DNA 可显著增加 MLN 中的 Tfh 频率，与 VP1 特异性 IgA 滴度相关。免疫后 24 小时，鼻腔内壳聚糖-DNA 诱导 CD103DC 募集到 MLN，同时在固有层 (LP) 中选择性丧失 CD103DC。激活的 MLN 衍生的 CD103DC 在壳聚糖-DNA 刺激下产生高水平的 IL-6 和 BAFF，这上调了 MLN B 细胞上的跨膜激活剂和钙调磷酸酶配体相互作用分子 (TACI) 的表达。在存在壳聚糖-DNA 的情况下与 IgMB 共培养时，MLN CD103DC 以 T 依赖性方式诱导 IgA 的产生；并且 CD103DC 的这种 IgA 促进作用可通过靶向 TACI 阻断，在较低程度上通过阻断 IL-6 阻断。MLN CD103DC 显示出增强的能力，可诱导增强的 CD4Th17 反应，并且缺乏 IL-17A 的小鼠在免疫后特异性肠道 IgA 显著减少。总之，肠系膜 CD103DC 对于壳聚糖增强 DNA 疫苗在肠道中特异性 IgA 转换的佐剂活性是必不可少的，通过激活 BAFF-TACI 和 IL-6-IL-6R 信号通路，以及通过在 MLN 中诱导 Th17/Tfh 分化。
