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

研究次级淋巴器官常驻记忆 T 细胞的丰度、命运和功能

基本信息

批准号：
10679775
负责人：
Stephen D O'Flanagan
金额：
$ 3.38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679775
关键词：
Address Anatomy Antigens Basic Science Biology Blood CD8-Positive T-Lymphocytes Cancer Biology Cells Cellular biology Data Dendritic Cells Deposition Development Disease Doctor of Philosophy Environment Faculty Fellowship Focal Infection Goals HIV Home Homing Human Immune response Immunity Immunologic Memory Immunologic Surveillance Immunology Infection Institution Intestines Investigation Laboratories Location Lymph Lymphocyte Malaria Mediating Memory Mentors Mesentery Microanatomy Microbe Microbiology Microscopy Minnesota Modeling Mus Operative Surgical Procedures Parabiosis Pathogenicity Perception Phenotype Play Population Positioning Attribute Proliferating Property Research Residencies Role Scientist Serology Signal Transduction Site Skin Systemic infection T memory cell T-Lymphocyte Techniques Testing Therapeutic Tissues Training Transplantation Tuberculosis Universities Vaccination Vaccine Design Vaccines Viral Virus Virus Diseases Virus Replication adaptive immunity biomarker identification career cell motility density developmental plasticity effector T cell emerging pathogen experience innovation intravital microscopy lymph nodes microbial migration mouse model multi-photon novel vaccines pathogen pathogen exposure pre-doctoral programs rapid detection residence secondary lymphoid organ tissue resident memory T cell

项目摘要

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.

项目摘要/摘要：尽管全球努力遏制新出现和重新出现的病原体，但疫苗设计的基本原理未能克服疟疾、艾滋病毒和结核病等毁灭性的顽固性疾病。自然感染或接种疫苗后，有助于防止再次感染。疫苗引发的 T 细胞免疫监视可能提供针对细胞内病原体的保护，并可能提供了一种增强体液介导疫苗的策略，然而，对记忆 CD8 T 细胞的深入了解。六十年来，迁移对于利用 T 细胞进行下一代疫苗设计至关重要。了解淋巴细胞通过血液和次级淋巴器官（SLO）进行再循环。记忆 T 细胞停泊在屏障组织的基质和实质区室中，称为常驻细胞记忆 T 细胞 (TRM) 主导非淋巴组织 (NLT) 监测并对比这一范式。中央记忆 T 细胞 (TCM) 通过血液和淋巴液迁移，我们和其他人最近表明 SLO 还由非再循环 TRM (SLO TRM) 进行巡逻，这可能构成对 LN 的重大重新评估 SLO TRM 在全身感染后广泛分布，可能有助于人类 LN 中记忆 T 细胞库的很大一部分，但 SLO TRM 在免疫中的作用是由于其独特的迁移特性，我认为 SLO TRM 在以下方面发挥着专门的作用。与循环记忆群体相比，记忆免疫反应将严格解决。经过不同病原体经历和鉴定后，SLO TRM 的丰度和显微解剖定位可靠地表示“脏”小鼠体内 LN 驻留的标记将检验 SLO TRM 的假设。并且，Aim 3 将在重新激活后迁移到其上游 NLT。再感染后的 SLO TRM 对疫苗设计和评估具有影响，这些研究将构成对 SLO TRM 生物学的一些初步研究最重要的是，该提案将作为一个理想的方案。我将在明尼苏达大学的实验室执行这项奖学金。 David Masopust 博士，记忆 T 细胞免疫监视研究领域的世界领先者。大学免疫学中心、微生物学、免疫学和癌症生物学博士的支持。计划和 Masopust 博士，我将接受个性化培训，以促进高效过渡到下一个阶段我的长期职业目标是在学术研究中获得教职。机构和指导创新基础科学，重点是免疫学。