Recent Thymic Emigrants of the CD4 T-cell Lineage

CD4 T 细胞谱系的最新胸腺迁移

• 批准号: 8212566
• 负责人: DAVID BRAM LEWIS
• 金额: $ 40.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212566
• 关键词: Accounting; Adult; Allogenic; B-Lymphocytes; Biological Assay; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Lineage; Cell physiology; Cells; Child; Clinical; Cytotoxic agent; DNA; DNA Sequence Rearrangement; Disease; Emigrant; Evaluation; Excision; Family; Flow Cytometry; Frequencies; Gene Expression; Gene Expression Profiling; Generations; Genes; Growth; HIV-1; Half-Life; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Immune system; Immunity; Impairment; In Vitro; Individual; Infant; Infection; Intervention; Joints; Kinetics; Knowledge; Label; Lymphopenia; Mature Thymocyte; Messenger RNA; Molecular Profiling; Monitor; Myasthenia Gravis; Neonatal; Output; PECAM1 gene; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Production; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Receptor-CD3 Complex, Antigen, T-Cell; Recovery; Research; Residual state; Role; SELL gene; Signal Transduction; Site; Stem cell transplant; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Thymectomy; Thymus Gland; Transplantation; Vaccines; base; congenital immunodeficiency; immune function; immunosenescence; in vivo; interest; mRNA Expression; member; memory CD4 T lymphocyte; novel; novel marker; peripheral blood; public health relevance; reconstitution; thymocyte; young adult

DESCRIPTION (provided by applicant): Antigenically naive CD4 expressing a¿-T cell receptors are critical for generating immune responses to neoantigens, and are produced de novo within the thymus as mature CD4+CD8- thymocytes. These enter the periphery to become recent thymic emigrants (RTEs) of the naive CD4 T-cell compartment. Although monitoring of CD4 RTEs is of great clinical interest, particularly in CD4 T-cell lymphopenia, direct evaluation of human CD4 RTEs has been limited by a lack of specific surface markers. This project will utilize a novel and recently identified surface marker for human CD4 RTEs, protein tyrosine kinase 7 (PTK7), to define CD4 RTE frequency, phenotype, and function. Preliminary results validate PTK7 as a CD4 RTE marker, and show that PTK7+ CD4 RTEs have a reduced capacity for effector function compared to PTK7- naive CD4 T cells. Aim 1 will use gene expression profiling by deep mRNA sequencing of unstimulated and stimulated PTK7+ CD4 RTEs and other CD4 T-lineage cells to: 1) define the extent of residual thymocyte gene expression in PTK7+ CD4 RTEs during ontogeny, and 2) identify gene products involved in reduced CD4 RTE immune function, particularly for Th1 generation and/or that subdivide PTK7+ CD4 RTEs into more versus less recent thymic emigrants. Aim 2 will use in vivo labeling to test the hypothesis that PTK7+ CD4 RTEs are the direct precursors of PTK7- naive CD4 T cells, and will determine the role of PTK7+ CD4 RTEs in maintaining naive CD4 T-cell numbers and 12-TCR repertoire diversity in HIV-1 infection. Aim 3 will use a similar approach to test the importance of PTK7+ CD4 RTEs in immune reconstitution of naive CD4 T cells after allogeneic hematopoietic stem cell transplantation. Aim 4 will define the kinetics of loss of PTK7+ CD4 RTEs in children and adults following complete thymectomy and the impact of this loss on naive CD4 T-cell numbers and 12- TCR repertoire diversity. Together, these studies will substantially enhance our understanding of the role of thymic RTE production in maintaining the peripheral naive CD4 T-cell compartment in health and disease. PUBLIC HEALTH RELEVANCE: The production of new CD4 T cells by the thymus, which are also known as CD4 recent thymic emigrants (RTEs), is important for the immune system to respond to infections and vaccines. This research will evaluate the production and function of CD4 RTEs, in healthy individuals and in patients with diseases or treatments that may alter RTE production; this knowledge will also help identify patients that might benefit by treatment with drugs to increase RTE production.

描述（由申请人提供）：表达 a¿ 的抗原性幼稚 CD4 -T 细胞受体对于产生针对新抗原的免疫反应至关重要，并且在胸腺内作为成熟的 CD4+CD8- 胸腺细胞重新产生，这些受体进入外周成为初始 CD4 T 细胞区室的新胸腺移民 (RTE)。尽管监测 CD4 RTE 具有很大的临床意义，特别是在 CD4 T 细胞淋巴细胞减少症中，但由于缺乏特定的表面，对人类 CD4 RTE 的直接评估受到限制。该项目将利用一种新的、最近鉴定的人类 CD4 RTE 表面标记，即蛋白酪氨酸激酶 7 (PTK7)，来定义 CD4 RTE 频率、表型和功能。初步结果验证了 PTK7 作为 CD4 RTE 标记。与 PTK7-naive CD4 T 细胞相比，PTK7+ CD4 RTE 的效应功能能力较低。目标 1 将通过深度 mRNA 测序来使用基因表达谱。未刺激和刺激的 PTK7+ CD4 RTE 和其他 CD4 T 谱系细胞：1) 确定个体发育过程中 PTK7+ CD4 RTE 中残留胸腺细胞基因表达的程度，以及 2) 识别参与降低 CD4 RTE 免疫功能的基因产物，特别是 Th1 代和/或将 PTK7+ CD4 RTE 细分为更多与更少最近的胸腺移出物，目标 2 将在体内使用。标记来测试PTK7+ CD4 RTE是PTK7-幼稚CD4 T细胞的直接前体的假设，并将确定PTK7+ CD4 RTE在维持HIV-1感染中幼稚CD4 T细胞数量和12-TCR库多样性中的作用。目标 3 将使用类似的方法来测试 PTK7+ CD4 RTE 在初始 CD4 T 细胞免疫重建中的重要性。目标 4 将确定儿童和成人完全胸腺切除术后 PTK7+ CD4 RTE 丢失的动力学，以及这种丢失对初始 CD4 T 细胞数量和 12-TCR 库多样性的影响。大大增强了我们对胸腺 RTE 产生在维持外周幼稚 CD4 T 细胞区室健康和疾病中的作用的理解。 公共健康相关性：胸腺产生的新 CD4 T 细胞（也称为 CD4 新胸腺移出物 (RTE)）对于免疫系统对感染和疫苗的反应非常重要。这项研究将评估其产生和功能。 CD4 RTE，在健康个体和患有可能改变 RTE 产生的疾病或治疗的患者中；这些知识也将有助于识别可能受益于增加 RTE 产生的药物治疗的患者。