ANALYSIS OF A NOVEL SUBSET OF HUMAN CD8+ MEMORY CELLS WITH STEM CELL QUALITIES

具有干细胞特性的新型人类 CD8 记忆细胞亚群的分析

• 批准号: 7832350
• 负责人: STANLEY R. RIDDELL
• 金额: $ 47.97万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7832350
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Acute; Acute Myelocytic Leukemia; Address; Adult; Age; Antigens; Area; Binding; CD8B1 gene; Cell surface; Cells; Characteristics; Clinical; Clinical Research; Communicable Diseases; Cytomegalovirus; Cytotoxic Chemotherapy; Databases; Development; Disease model; Drug resistance; Effector Cell; Exhibits; Exposure to; Fluorescent Dyes; Frequencies; Gene Expression; Gene Expression Profile; Grant; Granzyme; Hematopoiesis; Hematopoietic stem cells; Heterogeneity; Human; Human Herpesvirus 4; IL2RA gene; Immune response; Immunity; Immunization; Immunologics; In Vitro; Individual; Infection; KLRB1 gene; Latent Virus; Life; Longevity; Lymphoid; Lymphopenia; Maintenance; Malignant - descriptor; Malignant Neoplasms; Memory; Methods; Minor; Modeling; Molecular; Molecular Profiling; Mus; Nature; Organ; Patients; Peripheral; Phenotype; Proliferating; Property; Proteins; Recruitment Activity; Reporter; Resistance; Rhodamine 123; Role; SELL gene; Secondary Immunization; Sorting - Cell Movement; Stem cells; Systems Biology; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Transgenic Organisms; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Virus; Virus Diseases; Work; Xenobiotics; chemotherapy; daughter cell; experience; graft vs host disease; improved; in vivo; nonhuman primate; novel; novel strategies; pathogen; programs; public health relevance; reconstitution; resistance mechanism; self-renewal; terminally differentiated effector memory (TEM) T cells

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 04, Clinical Research and specific Challenge Topic 04-AI-102 - The human immune response to infection and immunization - Profiling via modern immunologic methods and systems biology. The development and maintenance of memory T cells is a hallmark of the host response to acute and persistent viral infections and a major objective of vaccination for infectious diseases and cancer. Analysis of the phenotype and function of memory T cells in both mice and humans has identified two broad subsets of long-lived memory cells termed central memory (TCM), defined by expression of CD45O and CD62L; and effector memory (TEM), defined by expression of CD45RO and the absence of CD62L. Recent work in the applicant's lab has identified a subset of quiescent memory CD8+ T cells in normal individuals that express cell surface markers that enable their separation from the more prevalent TCM and TEM subsets, and includes molecules shared by hematopoietic stem cells. These quiescent memory T cells exhibit higher ATP binding cassette (ABC) transporter activity, rapidly efflux fluorescent dyes and chemotherapy drugs and are resistant to cytotoxic chemotherapy in vitro and in vivo compared with the majority of memory T cells. The high-effluxing T cells have a diverse T cell receptor repertoire, contain T cells specific for persistent and acute viruses, and contribute to repopulation of memory T cells in individuals who have received chemotherapy. Preliminary gene expression arrays performed on sort-purified subpopulations of memory and na¿ve T cells demonstrate that the subsets of memory T cells with high efflux capacity have a distinct transcriptional profile compared with the majority of TM cells, and with TN cells. The studies in this challenge grant will deliver a detailed database on the frequency, functional properties and gene expression profile of these novel subsets of human antigen experienced T cells, and elucidate their development after vaccination. The potential impact of this work relates to improving our understanding of the mechanisms responsible for the durability of human CD8+ T memory in normal individuals and those undergoing chemotherapy or vaccination. The studies have implications for elucidating the nature of protective immunity that might be elicited by vaccines for infectious diseases and cancer, and could provide a marker for the integrity of host immunity to pathogens in aging. The specific aims are: Aim 1. To compare the frequency, transcriptional profile and factors governing maintenance and differentiation of chemotherapy resistant IL-18R?hi CD161hi subsets of human memory CD8+ T cells with IL-18Rlo CD161lo subsets of TCM and TEM, and with TN. The proposed studies will determine the frequency of CMhi and EMhi in normal adult humans (age 18-80), determine the transcriptional profile of these subsets in ten donors, and compare the functional properties of CMhi and EMhi with the respective non-effluxing subsets and with TN. Aim 2. To determine if primary or booster vaccination of humans with vaccinia virus induces a longlived subset of vaccinia virus-specific CD8+ CMhi and EMhi T cells. The time after infection or vaccination when this novel subset of IL18R?hi CD161hi virus-specific T cells might develop has not been defined. The proposed studies will examine the presence of vaccinia virus specific T cells in individuals with remote vaccinia immunization, recent vaccinia boosting and in vaccinia na¿ve individuals receiving a primary vaccination. PUBLIC HEALTH RELEVANCE: The development and maintenance of memory T cells is a hallmark of the host response to acute and persistent viral infections and a major objective of vaccination for infectious diseases and cancer. Progress in defining the qualitative attributes of memory T cells that contribute to their longevity has been much less significant, particularly in humans. Addressing these issues requires a greater understanding of the subsets of T cells that make up the human memory T cell pool and the application of novel approaches to interrogate the cellular and molecular programs that maintain these cells. The studies in this challenge grant will determine the frequency, functional properties and gene expression profile of novel subsets of human memory T cells that have characteristics of long-lived cells, and elucidate their development after vaccination. The potential impact of this work relates to improving our understanding of the mechanisms responsible for the durability of human CD8+ T memory in normal individuals and those undergoing chemotherapy or vaccination.

描述（由应用程序提供）：本申请解决广泛的挑战区域04，临床研究和特定挑战主题04-AI -102-对感染和免疫抑制的人类免疫响应 - 通过现代免疫方法和系统生物学进行分析。 记忆T细胞的发展和维持是宿主对急性和持续性病毒感染的反应的标志，也是传染病和癌症疫苗接种的主要目标。对小鼠和人类中记忆T细胞的表型和功能的分析已经确定了由CD45O和CD62L的表达定义的两个长寿命内存细胞（TCM）的两个广泛的子集；和效应子记忆（TEM），由CD45RO的表达和CD62L的缺失定义。适用的实验室中的最新工作已经确定了正常个体中静态记忆CD8+ T细胞的一部分，这些静态记忆CD8+ T细胞表达细胞表面标记，这些标记使其与更为普遍的TCM和TEMSet分离，并包括由血小质干细胞共享的分子。与大多数记忆T细胞相比，这些静止的记忆T细胞暴露了较高的ATP结合盒（ABC）转运蛋白活性，快速排出荧光染料和化学疗法药物，并且对体外和体内的细胞毒性化学疗法具有抵抗力。高效能的T细胞具有不同的T细胞受体库，其中包含特有的持续性和急性病毒的T细胞，并有助于接受化学疗法的个体中记忆T细胞的重生。与大多数TM细胞和TN细胞相比，对记忆和NA ve T细胞的排序纯化亚群的初步基因表达阵列表明，具有高流出能力的记忆T细胞的子集具有明显的转录曲线。这项挑战的研究将提供有关这些新型人类抗原经历T细胞的频率，功能特性和基因表达谱的详细数据库，并在疫苗接种后阐明了它们的发育。这项工作的潜在影响涉及我们对正常个体以及接受化学疗法或疫苗的人对人CD8+ T记忆持续性的机制的理解有关。这些研究对阐明保护性免疫的性质具有意义，这可能是由疫苗引起的传染病和癌症的，并且可以为宿主免疫学对衰老病原体的完整性提供标志性。具体目的是：目标1。要比较抗化疗的耐维持和分化IL-18R的频率，转录曲线和因素，即人类记忆CD8+ T细胞的抗化性IL-18R？拟议的研究将确定正常成年人中CMHI和EMHI的频率（18-80岁），确定这些子集中十个捐赠者中这些子集的转录曲线，并比较CMHI和EMHI的功能特性与各自的非效力子集的功能特性以及与TN。目的2。确定人类的原代或促进疫苗是疫苗病毒的疫苗是否会诱导长期存在的离子病毒特异性CD8+ CMHI和EMHI T细胞的子集。尚未定义感染或疫苗后的IL18R？HI CD161HI病毒特异性T细胞的新型子集的时间。拟议的研究将研究远距离牛ac疫苗免疫抑制，最近的疫苗促进以及接受原发性疫苗接种的个体中的离发率特定T细胞的存在。 公共卫生相关性：记忆T细胞的发展和维持是宿主对急性和持续性病毒感染的反应的标志，也是传染病和癌症疫苗接种的主要目标。定义有助于其寿命的记忆T细胞的定性属性的进展要少得多，尤其是在人类中。解决这些问题需要对构成人体记忆T细胞池的T细胞的子集有更多的了解，并采用新颖的方法来询问维持这些细胞的细胞和分子程序。这项挑战的研究将确定具有长寿命细胞特征的人类记忆T细胞的新型子集的频率，功能特性和基因表达谱，并在疫苗接种后阐明了它们的发育。 这项工作的潜在影响与我们提高对正常个体中人类CD8+ T记忆持续性的机制以及接受化学疗法或疫苗接种的机制有关。