Recent Thymic Emigrants of the CD4 T-cell Lineage

描述（由申请人提供）：表达a - t细胞受体的抗原性初始CD4对于产生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-胸腺细胞从头产生。这些细胞进入外周成为新生CD4 t细胞室的新近胸腺移植物（rte）。尽管监测CD4 rte具有重大的临床意义，特别是在CD4 t细胞淋巴细胞减少症中，但由于缺乏特异性表面标记物，对人类CD4 rte的直接评估受到限制。该项目将利用最近发现的一种新的人类CD4 RTE表面标记蛋白酪氨酸激酶7 （PTK7）来定义CD4 RTE频率、表型和功能。初步结果证实PTK7是CD4 RTE标志物，并表明与PTK7- naive CD4 T细胞相比，PTK7+ CD4 RTE的效应功能能力降低。目的1将通过对未受刺激和受刺激的PTK7+ CD4 RTE以及其他CD4 t谱系细胞进行深度mRNA测序来使用基因表达谱：1)确定PTK7+ CD4 RTE在个体发育过程中的残留胸腺细胞基因表达程度；2)鉴定与CD4 RTE免疫功能降低有关的基因产物，特别是Th1生成和/或将PTK7+ CD4 RTE细分为更近期或更近期的胸腺迁移。Aim 2将使用体内标记来验证PTK7+ CD4 rte是PTK7-初始CD4 T细胞的直接前体的假设，并将确定PTK7+ CD4 rte在维持HIV-1感染中初始CD4 T细胞数量和12-TCR库多样性中的作用。Aim 3将使用类似的方法来测试PTK7+ CD4 rte在同种异体造血干细胞移植后幼稚CD4 T细胞免疫重建中的重要性。目的4将定义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。总之，这些研究将大大增强我们对胸腺RTE产生在维持健康和疾病中外周初始CD4 t细胞区室中的作用的理解。

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.