Deficiency in Calcium-Binding Protein S100A4 Impairs the Adjuvant Action of Cholera Toxin.
Deficiency in Calcium-Binding Protein S100A4 Impairs the Adjuvant Action of Cholera Toxin.
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DOI：
10.3389/fimmu.2017.01119
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发表时间：
2017
影响因子：
7.3
通讯作者：
Xiang Z
中科院分区：
文献类型：
--
作者：
Sun JB;Holmgren J;Larena M;Terrinoni M;Fang Y;Bresnick AR;Xiang Z
已经描述了钙结合蛋白S100 A4促进实验性自身免疫性和炎性疾病以及变态反应中的病理性炎症，并且在用明矾佐剂化抗原进行肠胃外免疫后有助于抗原呈递和抗体应答。在这项研究中，我们扩展了这些发现，证明缺乏S100 A4的小鼠有缺陷的体液和细胞免疫应答粘膜（舌下）免疫与模型蛋白抗原[卵清蛋白（OVA）]与强粘膜佐剂霍乱毒素（CT），这种损害是由于缺陷的促炎剂刺激的抗原呈递细胞的抗原呈递。与野生型（WT）小鼠相比，在用OVA加CT免疫后，遗传上缺乏S100 A4的小鼠具有降低的体液和细胞免疫应答，包括完全缺乏可检测的生发中心反应。此外，当在体外用OVA加CT刺激时，S100 A4 −/−树突状细胞（DC）在几种CT刺激的免疫调节分子中显示出受损的反应，包括共刺激分子CD 86，炎性小体相关的caspase-1和IL-1β。与与WT DC的类似共培养物相比，OVA特异性OT-II T细胞与用OVA加CT脉冲孵育的S100 A4 −/− DC的共培养物导致OT-II T细胞增殖受损，Th 1、Th 2和Th 17细胞因子的产生减少。根据这些发现，用靶向S100 A4的小干扰RNA（siRNA）而不是模拟siRNA转染WT DC导致响应于CT的胱天蛋白酶-1和IL-1β以及CD 86的表达显著降低。重要的是，将WT DC植入S100 A4 −/−小鼠中也有效地恢复了受体对免疫的免疫应答。总之，我们的研究结果表明，在S100 A4的缺陷有强烈的影响，体液和细胞免疫的发展后，粘膜免疫CT作为佐剂。
The calcium-binding protein S100A4 has been described to promote pathological inflammation in experimental autoimmune and inflammatory disorders and in allergy and to contribute to antigen presentation and antibody response after parenteral immunization with an alum-adjuvanted antigen. In this study, we extend these findings by demonstrating that mice lacking S100A4 have a defective humoral and cellular immune response to mucosal (sublingual) immunization with a model protein antigen [ovalbumin (OVA)] given together with the strong mucosal adjuvant cholera toxin (CT), and that this impairment is due to defective adjuvant-stimulated antigen presentation by antigen-presenting cells. In comparison to wild-type (WT) mice, mice genetically lacking S100A4 had reduced humoral and cellular immune responses after immunization with OVA plus CT, including a complete lack of detectable germinal center reaction. Further, when stimulated in vitro with OVA plus CT, S100A4−/− dendritic cells (DCs) showed impaired responses in several CT-stimulated immune regulatory molecules including the co-stimulatory molecule CD86, inflammasome-associated caspase-1 and IL-1β. Coculture of OVA-specific OT-II T cells with S100A4−/− DCs that had been pulse incubated with OVA plus CT resulted in impaired OT-II T cell proliferation and reduced production of Th1, Th2, and Th17 cytokines compared to similar cocultures with WT DCs. In accordance with these findings, transfection of WT DCs with S100A4-targeting small interfering RNA (siRNA) but not mock-siRNA resulted in significant reductions in the expression of caspase-1 and IL-1β as well as CD86 in response to CT. Importantly, also engraftment of WT DCs into S100A4−/− mice effectively restored the immune response to immunization in the recipients. In conclusion, our results demonstrate that deficiency in S100A4 has a strong impact on the development of both humoral and cellular immunity after mucosal immunization using CT as adjuvant.