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: 10614040
• 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/10614040
• 关键词: Address; Affect; Antigen Presentation; Antigens; Archives; Attenuated Vaccines; Award; Bar Codes; CD8-Positive T-Lymphocytes; 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; Inflammation; Inflammatory; Lead; Learning; Lymphatic; Lymphatic Endothelial Cells; Measures; Memory; Messenger RNA; Methodology; Methods; Molecular; Process; Proliferating; 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; 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，来自传染性病毒感染的抗原在宿主体内持续存在， 延长的时间段，远远超过从宿主清除感染的时间。我们的实验室 特异性地鉴定了来源于疫苗接种和病毒感染的抗原持续存在或被存档， 宿主淋巴管内皮细胞（LEC），识别存档抗原的来源。我们已经发表 这种存档的抗原维持了更像效应子的抗原特异性记忆细胞库， 清除二次感染挑战。抗原相关关键机制的识别 疫苗接种期间的存档对于我们理解疫苗接种的增强保护性免疫至关重要。 虽然我们已经建立了抗原存档和保护性免疫的许多重要标准， 更新应用我们的目标是深入研究所涉及的细胞类型和所需的过程。我们的目标是 更好地理解亚群特异性基因的表达，现在发现在淋巴管内皮细胞和淋巴细胞中， 细胞和树突状细胞，可能需要抗原处理，这可能会影响抗原 存档和保护性豁免权我们已经建立了一种利用10倍基因组学的新方法， 这是一个鉴定DNA-抗原结合物的平台，用于研究抗原在长时间内的分散。与 有了这种方法和技术，我们现在就有能力准确、忠实地测量细胞生长情况。 获得抗原的类型以及随着时间的推移每个细胞内抗原的确切数量。使用这些 研究中，我们已经确定了几个新的发现的基础上抗原量和转录签名，导致 我们的假设是，特定的LEC和DC，基于他们的转录程序，有助于 抗原的获得、保留和交换。此外，LEC和DC对抗原的这种处理可以 被引起抗原释放和呈递的其他炎症事件操纵，结果， 改善对继发性和异源性感染的免疫应答。