Investigating the Abundance, Fate, and Function of Secondary Lymphoid Organ Resident Memory T cells

项目概要/摘要： 尽管全球都在努力减少新出现和重新出现的病原体，但合理的疫苗设计未能 战胜疟疾、艾滋病和结核病等毁灭性的疑难杂症。建立记忆T细胞 自然感染或接种疫苗后有助于防止再感染。因此，操纵 疫苗诱导的T细胞免疫监视可以提供针对细胞内病原体的保护， 提供了一种策略来支持体液介导的疫苗。然而，对记忆性CD 8 T细胞的深入了解 迁移对于开发用于下一代疫苗设计的T细胞将是至关重要的。六十年来，我们 了解淋巴细胞通过血液和次级淋巴器官（SLO）再循环。然而，在这方面， 记忆T细胞驻留在屏障组织的间质和实质区室中，称为驻留T细胞。 记忆T细胞（TRM），占主导地位的非淋巴组织（NLT）的监督和对比这一范式。虽然 中央记忆T细胞（TCM）通过血液和淋巴迁移，我们和其他人最近表明，SLO 也由非再循环TRM（SLO TRM）巡逻，这可能构成对LN的重大重新评估 免疫监视。SLO TRM在全身感染后广泛分布，可能导致 SLO TRM在人类LN中的记忆T细胞库中占相当大的比例，但SLO TRM在免疫中的作用是 未知由于它们独特的迁移特性，我假设SLO TRM在以下方面发挥专门作用： 与再循环记忆群体相比，回忆性免疫反应。目标1将严格解决 在不同病原体经历和鉴定后，SLO TRM丰度和显微解剖定位 这些标记物可靠地指示LN在“脏”小鼠中的驻留。目标2将检验SLO TRM是 在重新激活时准备迁移到它们的上游NLT。此外，目标3将解决 再次感染时SLO TRM。这些研究将对疫苗设计和评估产生影响， 一些对SLO TRM生物学的初步研究。最重要的是，这一建议将作为一个理想， 博士前培训的媒介。我将在明尼苏达大学的 大卫Masopust，博士，记忆T细胞免疫监视研究的世界领先者。与组合 该大学的免疫学中心，微生物学，免疫学和癌症生物学博士的支持。 程序，博士Masopust，我将接受个性化的培训，以促进有效过渡到下一个 我研究生涯的阶段。我的长期职业目标是在一家学术研究机构获得一个教职， 机构和直接创新基础科学，重点是免疫学。

Project Summary/Abstract: Despite global efforts to curtail emerging and reemerging pathogens, rationale vaccine design has failed to overcome devastating intractable diseases such as malaria, HIV, and tuberculosis. Memory T cells established after natural infection or vaccination contribute to protection against reinfection. Therefore, manipulating vaccine-elicited T cell immunosurveillance may provide protection against intracellular pathogens and might offer a strategy to bolster humoral-mediated vaccines. However, deep understanding of memory CD8 T cell migration will be critical to exploit T cells for next generation vaccine designs. For sixty years, we have understood that lymphocytes recirculate through blood and secondary lymphoid organs (SLO). However, memory T cells parked in the stromal and parenchymal compartments of barrier tissues, known as resident memory T cells (TRM), dominate nonlymphoid tissue (NLT) surveillance and contrast this paradigm. Although central memory T cells (TCM) migrate through blood and lymph, we and others have recently shown that SLO are also patrolled by nonrecirculating TRM ( SLO TRM), which may constitute a major reassessment of LN immunosurveillance. SLO TRM, are broadly distributed following systemic infections and may contribute a substantial fraction to the memory T cell pool in human LNs, but the roles of SLO TRM in immunity are unknown. Owing to their distinct migration properties, I hypothesize that SLO TRM play specialized roles in anamnestic immune responses compared to recirculating memory populations. Aim 1 will rigorously address the abundance and microanatomical localization of SLO TRM after diverse pathogen experiences and identify markers that reliably denote LN residence in ‘dirty’ mice. Aim 2 will test the hypothesis that SLO TRM are poised to migrate to their upstream NLT upon reactivation. And, Aim 3 will address the protective functions of SLO TRM upon reinfection. With implications for vaccine design and assessment, these studies will constitute some of the first investigations into SLO TRM biology. Most importantly, this proposal will serve as an ideal medium for predoctoral training. I will execute this fellowship at the University of Minnesota in the laboratory of David Masopust, Ph.D., a world-leader in the study of memory T cell immunosurveillance. With the combined support of the University’s Center for Immunology, the Microbiology, Immunology, and Cancer Biology Ph.D. program, and Dr. Masopust, I will receive personalized training to facilitate an efficient transition to the next stage of my research career. My long-term career goal is to obtain a faculty position at an academic research institution and direct innovative basic science with an emphasis in immunology.