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

项目摘要/摘要 在CD8 T细胞启动过程中，我们对促进 组织驻留记忆CD8T(TRM)细胞发育。在缺乏这样的知识的情况下，实现 发展疫苗接种策略，在病原体入侵或肿瘤部位激发强大的记忆T细胞 发展的可能性仍然很小。长期目标是确定调节诱导的机制。 并维护TRM细胞，以提高疫苗效力。此应用程序的总体目标是定义 预充如何影响肠道CD8 TRM细胞的原位发育。中心假设是，直接 肠道引流淋巴结中T细胞启动过程中的维甲酸信号允许CD8 TRM细胞在 肠子。这一假设是基于严格的初步数据，该数据表明维甲酸许可 CD8TRM前体细胞的发育不依赖于众所周知的CCR9介导的肠道迁移途径。 这项研究的理论基础是对促进CD8 TRM细胞的因素的了解 发展将为开发更有效和更有针对性的疫苗接种提供强有力的科学框架 战略。中心假说将通过追求三个具体目标来检验：1)检验假说 肠系膜淋巴结启动促进肠道CD103+CD8 TRM细胞分化；2)检测 假设维甲酸允许肠道CD103+CD8 TRM细胞发育；以及3)测试 假设膳食维生素A促进CD103+CD8 TRM细胞发育以提高疫苗效力。 MLN或脾来源的细胞将用于评估CD103+CD8 TRM细胞在肠道和远端的发育。 食源性感染后的组织。维甲酸受体(RAR)激动剂和拮抗剂与 RAR和CCR9基因敲除小鼠模型将被用来确定维甲酸如何许可肠道CD8 TRM细胞发育。最后，维生素A缺乏或补充的饮食将被用来调节维甲酸 并评估疫苗的免疫原性和效力。这项拟议的研究具有创新性，因为它利用 食源性感染适应人类病原体的单核细胞增生性李斯特氏菌，以询问肠道T 细胞反应。拟议的研究具有重要意义，因为它有望通过以下途径定义新的途径 哪种维甲酸独立于CCR9和肠道迁移影响肠道CD8 TRM细胞发育。 最终，这些知识可以应用于改进针对胃肠道的疫苗设计的基本原理。 维生素A缺乏的营养不良个体的病原体或免疫接种。

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.