Cooperation between lymphatic stroma and hematopoietic cells shapes protective immunity

淋巴基质和造血细胞之间的合作形成保护性免疫

• 批准号: 10443440
• 负责人: Beth Ann Tamburini
• 金额: $ 45.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-16 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443440
• 关键词: Address; Affect; Antigen Presentation; Antigens; Archives; Attenuated Vaccines; Award; Bar Codes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caveolins; Cell Communication; Cell Shape; Cell physiology; Cells; Cellular Immunity; Communication; Conjugate Vaccines; DNA; Data; Dendritic Cells; Development; Event; Exocytosis; Flow Cytometry; Funding; Future; Gene Expression Profile; Genes; Genetic Transcription; Hand; Hematopoietic; ICAM1 gene; Immune response; Immunity; Immunologic Memory; Infection; Inflammatory; Lead; Learning; Lymphatic; Lymphatic Endothelial Cells; Measures; Memory; Messenger RNA; Methodology; Methods; Molecular; Process; Proteins; Publishing; Secondary to; Signal Transduction; Source; Surface; T cell response; T memory cell; Techniques; Technology; Time; Tissues; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; adaptive immune response; antigen detection; base; cell type; design; emerging pathogen; genomic platform; grasp; improved; lymph nodes; novel; prevent; programs; protein degradation; secondary infection; single cell mRNA sequencing; subcutaneous; trafficking; transcriptome; vaccination strategy; vaccine strategy

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.

项目概要： 我们和其他人已经证明，源自传染性病毒感染的抗原在宿主体内持续存在 长时间，远远超过感染从宿主中清除的时间。我们实验室有 特别确定了源自疫苗接种和病毒感染的抗原持续存在或被存档 宿主淋巴内皮细胞 (LEC)，识别存档抗原的来源。我们已经发布了 这种存档的抗原维持了一个更像效应器的抗原特异性记忆细胞池，可以增强 清除继发性感染挑战。鉴定涉及抗原的关键机制 疫苗接种期间的存档对于我们了解增强的疫苗接种保护性免疫力至关重要。 虽然我们已经为抗原存档和保护性免疫制定了许多重要标准，但在这方面 更新应用程序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子集特异性基因的表达方式 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 归档和保护免疫。我们建立了一种利用 10x 基因组学的新颖方法 鉴定 DNA-抗原缀合物的平台，用于研究抗原的长期扩散。和 有了这种方法和技术，我们现在有能力准确、忠实地测量细胞 随着时间的推移，获得抗原的类型以及每个细胞内抗原的确切数量。使用这些 研究中，我们根据抗原量和转录特征确定了一些新发现，以引导 我们假设特定的 LEC 和 DC 基于其转录程序，有助于 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 受到导致抗原释放和呈递的其他炎症事件的操纵，因此， 改善对继发性和异源感染的免疫反应。