Recent Thymic Emigrants of the CD4 T-cell Lineage

表达T细胞受体(TCR)的抗原性CD4T细胞是产生 对新抗原的免疫反应，并在胸腺内成熟时从头产生 CD4+CD8-胸腺细胞。这些细胞进入外周，成为胸腺的新移民。 (Rtes)的原始CD4T细胞室。尽管对CD4RTE的监测是非常重要的 临床兴趣，例如，在CD4T细胞淋巴细胞减少的情况下，直接评估人类CD4RTE 由于缺乏特定的表面标记而受到限制。到目前为止，CD4RTE的产量 通过评估T细胞信号连接T细胞的含量间接地和不完全地推断 细胞受体切除环(SjTRECs)产生于胸腺内。这个项目将利用一部小说 最近发现了人类CD4rte的表面标志，蛋白酪氨酸激酶7(PTK7)， 确定CD4RTE的频率、表型和功能。初步结果证实PTK7是一种 CD4RTE标记，并显示PTK7+CD4RTE的效应器能力降低 与PTK7-NA和CD4T细胞的功能比较。目标1将使用基因表达谱分析 未刺激和刺激的PTK7+CD4rtes和其他CD4T细胞：1)定义 个体发育过程中PTK7+CD4rte中残留胸腺细胞基因表达的程度，以及2) 确定导致CD4RTE免疫功能降低的基因。这种方法还可以 揭示新的CD4RTE标志物。AIM 2将使用体内标记来确定PTK7+的寿命 CD4rte及其转化为成熟的PTK7-NAve CD4T细胞，并将决定 PTK7+CD4rte在维持天然CD4T细胞数量、sjTREC含量和 HIV-1感染中TCR谱系的多样性。Aim 3将使用类似的方法来测试 PTK7+CD4rtes在同种异体移植后天然CD4T细胞重建中的作用 造血干细胞移植。目标4将定义PTK7+CD4丢失的动力学 儿童和成人完全胸腺切除后的RTE，并将确定这种损失是如何 影响天然的CD4T细胞数量、sjTREC含量和TCR谱系的多样性。一起， 这些研究将大大增强我们对胸腺rte产生的作用的理解。 在健康和疾病中维持外周血中的天然CD4T细胞。

Antigenically-na¿ve CD4 T cells expressing ¿¿-T cell receptors (TCRs) are critical for generating immune responses to neoantigens, and are produced de novo within the thymus as mature CD4+CD8- thymocytes. These cells enter the periphery to become recent thymic emigrants (RTEs) of the na¿ve CD4 T-cell compartment. Although monitoring of CD4 RTEs is of great clinical interest, e.g., in cases of CD4 T-cell lymphopenia, direct evaluation of human CD4 RTEs has been limited by a lack of specific surface markers. Heretofore, CD4 RTE production has been indirectly and incompletely inferred by evaluating T cells for their content of signal joint T- cell receptor excision circles (sjTRECs) generated intrathymically. 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- na¿ve CD4 T cells. Aim 1 will use gene expression profiling 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 genes responsible for reduced CD4 RTE immune function. This approach may also reveal new CD4 RTE markers. Aim 2 will use in vivo labeling to determine the lifespan of PTK7+ CD4 RTEs and their conversion into mature PTK7- na¿ve CD4 T cells, and will determine the role of PTK7+ CD4 RTEs in maintaining na¿ve CD4 T-cell numbers, sjTREC content, and ¿¿- TCR repertoire diversity in HIV-1 infection. Aim 3 will use a similar approach to test the importance of PTK7+ CD4 RTEs in the reconstitution of na¿ve CD4 T cells following 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 will determine how this loss impacts na¿ve CD4 T-cell number, sjTREC content, and ¿¿-TCR repertoire diversity. Together, these studies will substantially enhance our understanding of the role of thymic RTE production in maintaining the peripheral na¿ve CD4 T-cell compartment in health and disease.