Immune Reconstitution

在过去，急性丧失后T细胞群重建的生物学特征并不完全。使用小鼠模型，我们首先确定了T细胞免疫重建的两个主要途径，经典的，胸腺依赖性途径，和第二个，胸腺非依赖性途径。然后，我们确定了T细胞表面标志物，其允许通过对重建的T细胞群体进行表型分析来识别产生它们的途径，然后将这些信息应用于患者T细胞重建的表征。最初的工作建立了这种方法在人类T细胞群体再生研究中的适用性。最近的工作验证了该方法的有效性，并建立了两种主要途径中每一种的成年人T细胞免疫重建过程。这项工作还显示了胸腺在定量再生CD 4 + T细胞中的重要作用。CD 8 + T细胞更强烈地依赖于外周扩增以进行免疫重建。CD 4+和CD 8 + T细胞都需要胸腺活性来维持或产生库多样性。这些发现反过来又导致研究重点放在了解控制胸腺功能的机制，以及新的治疗方法，包括疫苗策略，以在再生免疫系统的背景下治疗癌症。胸腺调节的四种模型已经开发出来;这项工作已经进展到两个新的研究项目领域的发展-一个集中在胸腺功能的调节点和一个在临床试验中引入代理。在这个项目中解决的工作也导致了在研究IL-7对胸腺细胞成熟的影响的努力。我们已经确定了IL-7作为胸腺生成的负调节因子以及对于胸腺细胞发育是必需的。这些双重作用是剂量依赖性的，并且在更高浓度下的负调节是通过Notch信号传导的控制介导的，Notch信号传导是T/B谱系定型的中心。此外，我们还努力鉴定可能调节胸腺的基因，并鉴定了一种名为Tbata（以前称为SPATIAL）的基因，它是一种在基质细胞室中起作用的负调节因子。它似乎通过控制细胞周期，特别是通过调节Nedd 8途径发挥其作用。雄激素信号传导阻断和IGF-1调节胸腺功能的细胞和分子机制的特点和地图点的增殖调节上皮细胞室的胸腺。一种新的转基因小鼠模型正在开发中，以调查参与这种调节的信号通路。

The biology of reconstitution of T cell populations following acute loss has, in the past, been incompletely characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. Initial work established the applicability of this approach to the study of T cell population regeneration in humans. Recent work verified validity of the approach and established the course of T cell immune reconstitution in adult humans over time for each of the two primary pathways. This work also showed an essential role for the thymus in regenerating CD4+ T cells quantitatively. CD8+ T cells depend more strongly on peripheral expansion for immune reconstitution. Both CD4+ and CD8+ T cells require thymic activity for maintenance or generation of repertoire diversity. These findings have led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments, including vaccine strategies, to treat cancer in the setting of a regenerating immune system. Four models of thymic regulation have been developed; this work has progressed to the developoment of two new project areas of research -- one focused on points of regulation of thymus function and one on introducing agents into clinical trials. The work addressed in this project has also led to efforts in investigating IL-7 effects on the maturation of thymocytes. We have identified IL-7 as a negative regulator of thymopoiesis as well as being essential for thymocyte development. These dual roles are dose dependent and negative regulation at higher concentrations is mediated through control of Notch signaling -- which is central to T/B lineage commitment. Additionally, we have worked to identify genes which might regulate the thymus, and have characterized a gene called Tbata (previously SPATIAL) which is a negative regulator acting within the stromal cell compartment. It appears to exert its effect through control of cell cycle, specifically through regulation of the Nedd8 pathway. The cellular and molecular mechanisms by which androgen signaling blockade and IGF-1 modulate thymus function were characterized and map points of regulation of proliferation to the epithelial cell compartment of the thymus. A new transgenic murine model is being developed to investigate signaling pathways involved in this regulation.