Recent Thymic Emigrants of the CD4 T-cell Lineage

描述（由申请方提供）：表达α-T细胞受体的抗原初始CD 4对于产生对新抗原的免疫应答至关重要，并且在胸腺内作为成熟的CD 4 + CD 8-胸腺细胞从头产生。这些细胞进入外周，成为初始CD 4 T细胞区室的近期胸腺移出物（RTE）。虽然监测CD 4 RTEs具有很大的临床意义，特别是在CD 4 T细胞淋巴细胞减少症中，但由于缺乏特异性表面标志物，对人CD 4 RTEs的直接评价受到限制。该项目将利用一种新的和最近发现的人类CD 4 RTE的表面标志物，蛋白酪氨酸激酶7（PTK 7），以确定CD 4 RTE的频率，表型和功能。初步结果验证了PTK 7作为CD 4 RTE标志物，并显示PTK 7 + CD 4 RTE与PTK 7初始CD 4 T细胞相比具有降低的效应子功能能力。目的1将通过未刺激和刺激的PTK 7 + CD 4 RTE和其他CD 4 T谱系细胞的深度mRNA测序，使用基因表达谱分析：1）确定个体发育期间PTK 7 + CD 4 RTE中残留胸腺细胞基因表达的程度，和2）鉴定参与降低的CD 4 RTE免疫功能的基因产物，特别是对于Th 1产生和/或将PTK 7 + CD 4 RTE细分为更多与更少最近的胸腺移出者。目的2将使用体内标记来检验PTK 7 + CD 4 RTEs是PTK 7- naive CD 4 T细胞的直接前体的假设，并将确定PTK 7 + CD 4 RTEs在维持HIV-1感染中的naive CD 4 T细胞数量和12-TCR库多样性中的作用。目的3将使用类似的方法来测试PTK 7 + CD 4 RTEs在异基因造血干细胞移植后初始CD 4 T细胞的免疫重建中的重要性。目的4将确定胸腺完全切除术后儿童和成人PTK 7 + CD 4 RTE丢失的动力学，以及这种丢失对初始CD 4 T细胞数量和12- TCR库多样性的影响。总之，这些研究将大大提高我们对胸腺RTE产生在维持健康和疾病中外周幼稚CD 4 T细胞区室中的作用的理解。 公共卫生相关性：胸腺产生新的CD 4 T细胞，也称为CD 4近期胸腺移行细胞（RTE），对于免疫系统对感染和疫苗的反应至关重要。这项研究将评估健康个体和患有可能改变RTE生产的疾病或治疗的患者中CD 4 RTE的生产和功能;这些知识也将有助于确定可能通过药物治疗获益的患者，以增加RTE生产。

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.