Immune Reconstitution

过去，T 细胞群在急性损失后重建的生物学特征尚未完全确定。使用小鼠模型，我们首先确定了 T 细胞免疫重建的两条主要途径，即经典的胸腺依赖性途径和第二条胸腺非依赖性途径。然后，我们鉴定了 T 细胞表面标记，通过对重建的 T 细胞群进行表型分析，可以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。初步工作确立了该方法在人类 T 细胞群再生研究中的适用性。最近的工作验证了该方法的有效性，并确定了成年人体内两种主要途径随时间推移的 T 细胞免疫重建过程。这项工作还显示了胸腺在 CD4 T 细胞定量再生中的重要作用。 CD8 T 细胞更强烈地依赖外周扩张来进行免疫重建。 CD4 和 CD8 T 细胞都需要胸腺活性来维持或产生库多样性。这些发现反过来导致研究重点放在了解控制胸腺功能的机制，以及在免疫系统再生的情况下治疗癌症的新疗法，包括疫苗策略。已开发出四种胸腺调节模型；这项工作已发展为两个新项目研究领域的发展——一个侧重于胸腺功能的调节点，另一个侧重于将药物引入临床试验。该项目中涉及的工作还导致了研究 IL-7 对胸腺细胞成熟的影响的努力。我们已确定 IL-7 是胸腺生成的负调节因子，并且对于胸腺细胞的发育至关重要。这些双重作用是剂量依赖性的，较高浓度下的负调节是通过控制 Notch 信号传导介导的，这对于 T/B 谱系定型至关重要。此外，我们还致力于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，该基因是在基质细胞区室中发挥作用的负调节因子。它似乎通过控制细胞周期发挥作用，特别是通过调节 Nedd8 途径。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得到了表征，并将增殖调节点映射到胸腺的上皮细胞区室。一种新的转基因小鼠模型正在开发中，以研究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.