Cooperation between lymphatic stroma and hematopoietic cells shapes protective immunity

项目总结： 我们和其他人已经证明，来自传染性病毒感染的抗原在宿主体内持续存在 延长的时间，远远超过从宿主清除感染的时间。我们的实验室有 明确指出，来自疫苗接种和病毒感染的抗原持续存在或由 宿主淋巴管内皮细胞S，鉴定存档抗原的来源。我们已经出版了 这种存档的抗原维持着一个更像抗原特异性记忆细胞池的效应器，它增强了 第二次传染性挑战的清除。识别与抗原有关的关键机制 疫苗接种期间的存档对于我们理解加强疫苗接种的保护性免疫至关重要。 虽然我们已经为抗原存档和保护性免疫建立了许多重要的标准，但在这方面 续期申请我们的目标是更深入地研究所涉及的细胞类型和所需的过程。我们的目标是 更好地理解现在在淋巴管内皮细胞中发现的亚群特异性基因的表达 细胞和树突状细胞，可能是抗原处理所必需的，其影响可能会影响抗原 存档和保护豁免权。我们已经建立了一种利用10倍基因组学的新方法 鉴定DNA-抗原结合物的平台，用于研究抗原在较长时间内的扩散。使用 有了这种方法和技术，我们现在有能力准确而忠实地测量细胞 获取抗原的类型以及随时间推移每个细胞内的确切抗原数量。使用这些 研究中，我们根据抗原量和转录签名确定了几个新的发现 我们支持这样的假设，即特定的LEC和DC，基于它们的转录程序，对 抗原的获取、保留和交换。此外，LEC和DC对抗原的这种处理可以 被其他导致抗原释放和呈递的炎性事件操纵，因此， 提高对继发感染和异源感染的免疫反应。

Project summary: We and others have demonstrated that antigens derived from infectious viral infections persist in the host for extended periods of time, well beyond the time in which the infection is cleared from the host. Our lab has specifically identified that antigens derived from both vaccination and viral infections persist or are archived by the host lymphatic endothelial cells (LEC)s, identifying the source of archived antigens. We have published that this archived antigen maintains a more effector like pool of antigen specific memory cells which enhances the clearance of a secondary infectious challenge. Identification of key mechanisms involved in antigen archiving during vaccination is critical for our understanding of enhanced protective immunity to vaccination. While we have established many important criteria for antigen archiving and protective immunity, in this renewal application we aim to dive deeper into the cell types involved and the processes required. We aim to better appreciate how the expression of subset specific genes, now discovered in both lymphatic endothelial cells and dendritic cells, may be required for antigen handling, the implications of which could affect antigen archiving and protective immunity. We have established a novel methodology leveraging the 10x genomics platform to identify DNA-antigen conjugates for the study of antigen dispersal over long periods of time. With this methodology and technology in hand we now have the capability to accurately and faithfully measure cell types that acquire antigens as well as the exact number of antigens within each cell over time. Using these studies we have identified several novel findings based on antigen amount and transcriptional signature to lead us to the hypothesis that specific LECs and DCs, based on their transcriptional program, contribute to the acquisition, retention and exchange of antigens. Furthermore, this handling of antigens by LECs and DCs can be manipulated by other inflammatory events that cause antigen release and presentation, and as a result, improve immune responses to secondary and heterologous infections.