The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo.
The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo.
复制标题
粘膜辅助循环DI-GMP增强了抗原摄取，并选择性地激活了体内的性腺增生效率细胞。
作者：
Blaauboer SM;Mansouri S;Tucker HR;Wang HL;Gabrielle VD;Jin L
有效的粘膜佐剂可提高疫苗应答的程度和质量。环二GMP（CDG）是一种很有前途的粘膜疫苗佐剂。然而，其体内机制尚不清楚。在此，我们发现，在小鼠中，CDG比哺乳动物2′3′-环GMP-AMP（cGAMP）激发更强的Ab和TH应答，并且比2′3′-cGAMP佐剂疫苗产生更好的对肺炎链球菌感染的保护作用。我们确定了两个在体内的CDG机制。首先，鼻内给药的CDG大大提高了银的吸收，包括胞饮和受体介导的内吞作用在体内。这种增强依赖于CD 11 C+细胞中MPYS（STING，MITA）的表达。第二，我们发现CDG选择性激活胞饮有效的DC，导致TH极化细胞因子IL-12 p70、IFNγ、IL-5、IL-13、IL-23和IL-6在体内产生。值得注意的是，CDG在体内诱导IFNλ，但不诱导IFNβ。我们的研究揭示了MPYS以前未被认识的体内功能，并推进了我们对CDG作为粘膜疫苗佐剂的理解。DOI：http://dx.doi.org/10.7554/eLife.06670.001细菌、病毒或其他病原体在体内的存在通常会引发人体免疫系统的反应。除了试图摧毁感染因子外，免疫系统还将产生“记忆细胞”，这些细胞已经准备好识别并帮助消除病原体，如果它再次遇到的话。记忆细胞识别的入侵者的部分被称为抗原。疫苗是一种生物制剂，可以提高对特定疾病的免疫力。疫苗通常含有死亡或弱化的病原体，或其毒素或表面蛋白。这会使免疫系统以无害的方式暴露于抗原，并产生记忆细胞，这些细胞能够在未来个体因感染而生病之前对抗有害的病原体。称为佐剂的物质也必须添加到许多现代疫苗中。佐剂有助于将抗原呈递给免疫细胞，并通过这样做刺激更强和更有针对性的免疫反应。虽然目前许多疫苗都是注射的，但人们对开发和改进可吸入疫苗的兴趣越来越大。这将疫苗直接传递到鼻子和肺部的粘膜表面，这是一种更有效的方式来产生对某些细菌和病毒的免疫力。由于这些粘膜疫苗也相对便宜和易于应用，它们也适用于发展中国家和紧急情况。目前许可的肺炎球菌疫苗不能提供针对感染的强粘膜保护。因此，肺炎球菌疾病造成的死亡人数超过所有疫苗可预防疾病的总和。开发安全有效的粘膜疫苗佐剂是减少肺炎球菌疾病影响的关键。环状二GMP是一种主要存在于细菌中的分子，是一种强大的粘膜佐剂。然而，在它可以广泛用于疫苗之前，首先需要知道环二GMP如何刺激免疫系统。Blaauboer，Mandarin等人研究了小鼠对通过鼻施用的环状二GMP的免疫应答。这揭示了环二GMP增强人体对疫苗免疫反应的两种方式。首先，环状二GMP提高了暴露于疫苗的某些细胞对抗原的吸收，这一过程确保了大量细胞会提醒免疫系统注意所感知的威胁。其次，Blaauboer，Mandarin等人解释说，环状二GMP选择性地激活称为树突状细胞的免疫细胞，然后产生称为细胞因子的蛋白质，这些蛋白质向其他细胞发出信号并协调免疫反应。一种称为STING（干扰素基因刺激因子）的基因控制环状二GMP诱导的抗原摄取和树突状细胞的活化。现在需要对这些过程进行进一步研究，以调查环状二GMP是否是人类合适的粘膜肺炎球菌疫苗佐剂。DOI：http://dx.doi.org/10.7554/eLife.06670.002网站
Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed, in mice, that CDG elicits stronger Ab and TH responses than the mammalian 2′3′-cyclic GMP-AMP (cGAMP), and generated better protection against Streptococcus pneumoniae infection than 2′3′-cGAMP adjuvanted vaccine. We identified two in vivo mechanisms of CDG. First, intranasally administered CDG greatly enhances Ag uptake, including pinocytosis and receptor-mediated endocytosis in vivo. The enhancement depends on MPYS (STING, MITA) expression in CD11C+ cells. Second, we found that CDG selectively activated pinocytosis-efficient-DCs, leading to TH polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23, and IL-6 production in vivo. Notably, CDG induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of CDG as a mucosal vaccine adjuvant. DOI: http://dx.doi.org/10.7554/eLife.06670.001 The presence of a bacterium, virus, or other pathogen in the body generally triggers a response by the body's immune system. As well as trying to destroy the infectious agent, the immune system will also generate ‘memory cells’ that are primed and ready to recognize and help eliminate the pathogen if it is ever re-encountered. The parts of the invader that the memory cells recognize are called antigens. A vaccine is a biological preparation that improves immunity to a particular disease. Vaccines normally contain a dead or weakened version of a pathogen, or its toxins or surface proteins. This exposes the immune system to the antigens in a harmless way, and creates memory cells that are able to fight off the harmful pathogen in the future before the individual becomes ill from the infection. Substances called adjuvants must also be added to many modern vaccines. Adjuvants help to present antigens to immune cells, and by doing so stimulate a stronger and more targeted immune response. While many vaccines are currently injected, there is growing interest in developing and improving vaccines that can be inhaled. This delivers the vaccine directly to the mucosal surfaces that line the nose and lungs, which is a more effective way to produce immunity against certain bacteria and viruses. As these mucosal vaccines are also relatively cheap and easy to apply, they would also be suitable for use in developing countries and during emergencies. Current licensed pneumococcal vaccines do not provide strong mucosal protection against the infection. As a result, pneumococcal diseases kill more people than all vaccine-preventable diseases combined. Developing safe and effective mucosal vaccine adjuvants is key to reducing the impact of pneumococcal diseases. Cyclic di-GMP, a molecule found primarily in bacteria, is a powerful mucosal adjuvant. However, before it can be widely used in vaccines, it first needs to be known how cyclic di-GMP stimulates the immune system. Blaauboer, Mansouri et al. studied the immune response of mice to cyclic di-GMP applied through the nose. This revealed two ways that cyclic di-GMP enhances the body's immune response to a vaccine. First, cyclic di-GMP improves the uptake of antigens by certain cells exposed to the vaccine, a process that ensures a large number of cells will alert the immune system to the perceived threat. Second, Blaauboer, Mansouri et al. explain that cyclic di-GMP selectively activates immune cells known as dendritic cells, which then produce proteins called cytokines that signal to other cells and coordinate the immune response. A gene called STING (stimulator of interferon genes) controls both cyclic di-GMP induced antigen uptake and the activation of dendritic cells. Further research into these processes is now needed to investigate whether cyclic di-GMP is a suitable mucosal pneumococcal vaccine adjuvant for humans. DOI: http://dx.doi.org/10.7554/eLife.06670.002