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: 10724082
• 负责人: Beth Ann Tamburini
• 金额: $ 2.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724082
• 关键词: Affect; Antigens; Archives; Cell Shape; Cell physiology; Cells; Communication; DNA; Dendritic Cells; Event; Gene Expression Profile; Genes; Genetic Transcription; Hand; Hematopoietic; Immune response; Immunity; Infection; Inflammatory; Lymphatic; Lymphatic Endothelial Cells; Measures; Memory; Methodology; Process; Publishing; Secondary to; Source; Technology; Time; Vaccination; Virus Diseases; cell type; genomic platform; improved; novel; programs

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.

项目摘要： 我们和其他人已经证明，从传染性病毒感染中得出的抗原持续存在于宿主中 长时间的时间，远远超出了从宿主清除感染的时间。我们的实验室有 明确确定从疫苗接种和病毒感染中得出的抗原持续存在或由 宿主淋巴内皮细胞（LEC）S，识别存档的抗原来源。我们已经出版了 该存档的抗原保持更大的效应子，例如抗原特定记忆细胞的池，从而增强 次要传染性挑战的清除。识别抗原涉及的关键机制 疫苗接种期间的归档对于我们了解增强的保护性免疫对疫苗接种至关重要。 尽管我们建立了许多抗原归档和保护性免疫的重要标准，但 我们旨在深入研究所涉及的细胞类型和所需过程。我们的目标 更好地欣赏该子集特定基因的表达，现在在两个淋巴内皮中都发现了 抗原处理可能需要细胞和树突状细胞，其影响可能影响抗原 归档和保护性免疫。我们已经建立了一种利用10倍基因组学的新方法 识别DNA抗原结合物以研究抗原分散的平台。和 该方法和技术手头，我们现在有能力准确，忠实地测量细胞 随着时间的推移，获取抗原以及每个细胞中的确切抗原数量的类型。使用这些 研究我们已经根据抗原量和转录签名确定了几个新发现，以引导 我们认为，特定的LEC和DC基于其转录计划，有助于 抗原的获取，保留和交换。此外，通过LEC和DC对抗原的处理可以 通过引起抗原释放和表现的其他炎症事件来操纵，结果 改善对继发和异源感染的免疫反应。