Impact of priming on the generation of intestinal tissue-resident memory T cells

启动对肠道组织驻留记忆 T 细胞生成的影响

• 批准号: 10707171
• 负责人: Brian S Sheridan
• 金额: $ 50.91万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707171
• 关键词: Agonist; Attenuated; CCR9 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Data; Dendritic Cells; Development; Diet; Disease; Distal; Event; Gastrointestinal Neoplasms; Generations; Goals; Immune response; Immunity; Immunization; In Situ; Individual; Infection; Inflammatory Bowel Diseases; Integrins; Intestines; Invaded; Knockout Mice; Knowledge; Licensing; Listeria monocytogenes; Lymphoid Tissue; Maintenance; Malnutrition; Mediating; Memory; Mission; Molecular; Mus; Outcome; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Public Health; Research; Residencies; Retinoic Acid Receptor; Signal Transduction; Site; Spleen; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Tissues; Tretinoin; United States National Institutes of Health; Vaccine Design; Vaccines; Vitamin A; Vitamin A Deficiency; antagonist; dietary; draining lymph node; experimental study; foodborne; foodborne infection; gastrointestinal; human pathogen; improved; innovation; intestinal epithelium; mesenteric lymph node; migration; mouse model; novel; oral vaccine; pathogen; precursor cell; targeted treatment; therapy development; tissue resident memory T cell; tumor; vaccination strategy; vaccine efficacy; vaccine immunogenicity; vaccine platform

PROJECT SUMMARY/ABSTRACT There is a critical gap in our knowledge of the mechanisms during CD8 T cell priming that promote tissue-resident memory CD8 T (TRM) cell development. In the absence of such knowledge, the realization of developing vaccination strategies that elicit robust memory T cells at sites of pathogen invasion or tumor development remain unlikely. The long-term goal is to determine the mechanisms that regulate the induction and maintenance of TRM cells to improve vaccine efficacy. The overall objective in this application is to define how priming influences the in situ development of intestinal CD8 TRM cells. The central hypothesis is that direct retinoic acid signals during T cell priming in the gut draining lymph nodes license CD8 TRM cell development in the intestine. This hypothesis is based on rigorous preliminary data that suggests that retinoic acid licenses CD8 TRM precursor cell development independent of the well known CCR9-mediated gut migration pathway. The rationale that underlies the proposed research is that knowledge of the factors that promote CD8 TRM cell development will provide a strong scientific framework to develop more effective and targeted vaccination strategies. The central hypothesis will be tested by pursuing three specific aims: 1) To test the hypothesis that priming in mesenteric lymph nodes promotes intestinal CD103+ CD8 TRM cell differentiation; 2) To test the hypothesis that retinoic acid licenses intestinal CD103+ CD8 TRM cell development; and 3) To test the hypothesis that dietary vitamin A enhances CD103+ CD8 TRM cell development to improve vaccine efficacy. MLN or spleen derived cells will be used to assess CD103+ CD8 TRM cell development in the gut and in distal tissues after foodborne infection. Agonists and antagonists of retinoic acid receptors (RAR) in combination with RAR and CCR9 knockout mouse models will be used to determine how retinoic acid licenses intestinal CD8 TRM cell development. Finally, vitamin A deficient or supplemented diets will be used to modulate retinoic acid and assess vaccine immunogenicity and efficacy. The proposed research is innovative because it utilizes foodborne infection with a mouse adapted human pathogen, Listeria monocytogenes, to interrogate intestinal T cell responses. The proposed research is significant because it is expected to define novel pathways through which retinoic acid impacts intestinal CD8 TRM cell development independent of CCR9 and gut migration. Ultimately, such knowledge can be applied to improve rationale vaccine design targeting gastrointestinal pathogens or immunization in malnourished individuals with vitamin A deficiency.

项目总结/摘要 在我们对CD 8 T细胞启动过程中促进T细胞增殖的机制的认识中存在着一个关键的空白。 组织驻留记忆CD 8 T（TRM）细胞发育。如果没有这种知识， 开发疫苗接种策略，在病原体入侵或肿瘤部位引发强大的记忆T细胞 发展不太可能。长期目标是确定调节诱导的机制 和维持TRM细胞以提高疫苗效力。本申请的总体目标是定义 引发如何影响肠道CD 8 TRM细胞的原位发育。核心假设是， 在肠道引流淋巴结中T细胞引发期间的视黄酸信号许可CD 8 TRM细胞发育， 肠子这一假设是基于严格的初步数据，表明视黄酸许可， CD 8 TRM前体细胞发育独立于众所周知的CCR 9介导的肠道迁移途径。 提出的研究的基本原理是，对促进CD 8 TRM细胞增殖的因素的了解， 发展将为开发更有效和更有针对性的疫苗提供强有力的科学框架 战略布局中心假设将通过追求三个具体目标来检验：1）检验假设， 在肠系膜淋巴结中的引发促进肠CD 103 + CD 8 TRM细胞分化; 2）为了测试肠CD 103 + CD 8 TRM细胞的分化， 假设视黄酸许可肠CD 103 + CD 8 TRM细胞发育;和3）为了测试 膳食维生素A增强CD 103 + CD 8 TRM细胞发育以提高疫苗效力的假说。 MLN或脾源性细胞将用于评估肠道和远端中的CD 103 + CD 8 TRM细胞发育。 食源性感染后的组织。视黄酸受体（RAR）的激动剂和拮抗剂与 RAR和CCR 9敲除小鼠模型将用于确定视黄酸如何许可肠道CD 8 TRM细胞发育。最后，维生素A缺乏或补充饮食将用于调节视黄酸 并评估疫苗的免疫原性和有效性。这项研究是创新的，因为它利用了 食源性感染的小鼠适应人类病原体，李斯特菌，询问肠道T 细胞反应。这项拟议中的研究意义重大，因为它有望通过以下途径定义新的途径： 其中视黄酸影响肠CD 8 TRM细胞发育，而不依赖于CCR 9和肠迁移。 最终，这些知识可以应用于改进靶向胃肠道的疫苗设计 病原体或免疫营养不良的人与维生素A缺乏症。