Recent Thymic Emigrants of the CD4 T-cell Lineage

描述(由申请人提供)：抗原性幼稚的CD4表达α-T细胞受体是产生对新抗原的免疫反应的关键，并在胸腺内从头产生成熟的CD8-胸腺细胞。这些细胞进入外周，成为幼稚的CD4T细胞隔间的新近的胸腺移民者(RTE)。虽然对CD4RTES的监测具有很大的临床意义，特别是在CD4T细胞淋巴细胞减少症中，但由于缺乏特定的表面标志物，对人类CD4RTES的直接评估一直受到限制。该项目将利用最近发现的人类CD4RTE的一种新的表面标志--蛋白酪氨酸激酶7(PTK7)来确定CD4RTE的频率、表型和功能。初步结果证实PTK7是一种CD4RTE标记物，并显示与PTK7-naive CD4T细胞相比，PTK7CD4rte的效应功能能力降低。目的1)通过对未受刺激和受刺激的PTK7CD4RTE和其他CD4T细胞进行基因表达谱分析：1)确定PTK7CD4RTE在个体发育过程中残留胸腺细胞基因表达的程度，以及2)识别与CD4RTE免疫功能降低有关的基因产物，特别是Th1的产生和/或将PTK7CD4RTE细分为更多和更少的胸腺迁移者。目的2将利用体内标记来验证PTK7-CD4rte是PTK7-初始CD4T细胞的直接前体的假设，并将确定PTK7CD4rtes在维持HIV-1感染的初始CD4T细胞数量和12TCR谱系多样性中的作用。目的3将使用类似的方法来测试PTK7CD4rtes在异基因造血干细胞移植后初始CD4T细胞免疫重建中的重要性。目的4将确定儿童和成人完全胸腺切除后PTK7CD4rte丢失的动力学，以及这种丢失对初始CD4T细胞数量和12-TCR谱系多样性的影响。总之，这些研究将极大地增强我们对胸腺RTE产生在维持健康和疾病中外周原始CD4T细胞隔间中的作用的理解。 公共卫生相关性：胸腺产生新的CD4T细胞，也被称为CD4近期胸腺移民(RTES)，对于免疫系统对感染和疫苗的反应是重要的。这项研究将评估健康个体和患有疾病或可能改变RTE产生的治疗的患者的CD4RTE的产生和功能；这一知识还将有助于确定那些可能受益于增加RTE产生的药物治疗的患者。

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.