Mapping the early thymic progenitor niche

血液系统的恶性疾病，如白血病，可以通过造血干细胞移植（HSCT）在破坏患者的肿瘤细胞以及他的造血系统之后成功地治疗。然而，HSCT经常伴随着免疫缺陷的延长期，这导致急性细菌和真菌感染以及潜伏病毒再活化的危险增加。免疫缺陷的这一阶段主要是由于适应性免疫系统和T细胞的缓慢恢复。因此，更好地理解T细胞发育和再生的分子和细胞机制以设计策略来改善HSCT后的T细胞重建是至关重要的。T细胞发育发生在胸腺中，但该过程严格依赖于从骨髓中募集祖细胞。我们以前的特点是多个祖细胞群，能够进入胸腺，并产生T细胞。此外，我们已经确定趋化因子受体CCR7和CCR9作为祖细胞进入的关键介质。祖细胞向胸腺的募集受到严格的调控，但限制进入胸腺的分子和细胞反馈机制仍然知之甚少。在这里，我们计划使用一种新的小鼠模型结合细胞条形码来跟踪单个祖细胞的后代，以表征祖细胞进入的最早阶段。这些工具将使我们能够直接确定在健康和疾病条件下进入胸腺的祖细胞数量，将进入胸腺组织与早期扩张阶段分开，并确定限制祖细胞进入的细胞和分子反馈回路。此外，本实验将使我们能够阐明一个极具争议的问题，即胸腺微环境是否允许非T细胞发育。总之，本实验将促进我们对生理和病理条件下T细胞发育的最早期事件的理解，从而为改善HSCT后T细胞重建指明新的方向。

Malignant diseases of the blood system, such as leukemias, can be successfully treated by hematopoietic stem cell transplantation (HSCT) following destruction of the patient's tumor cells but also his hematopoietic system. However, HSCT is frequently accompanied by a prolonged phase of immunodeficiency, which results in an increased danger of acute bacterial and fungal infections and reactivation of latent viruses. This phase of immunodeficiency is largely due to slow recovery of the adaptive immune system and T cells in particular. Therefore, it is critical to better understand the molecular and cellular mechanisms of T cell development and regeneration to devise strategies to improve T cell reconstitution after HSCT.T cell development occurs in the thymus, but this process is strictly dependent on the recruitment of progenitor cells from the bone marrow. We have previously characterized multiple progenitor cell populations that are able to enter the thymus and give rise to T cells. Furthermore, we have identified the chemokine receptors CCR7 and CCR9 as critical mediators of progenitor entry. Recruitment of progenitor cells to the thymus is tightly regulated, but molecular and cellular feedback mechanisms that restrict entry into the thymus remain poorly understood. Here, we plan to characterize the earliest phase of progenitor entry using a novel mouse model in combination with cellular bar coding to track the offspring of individual progenitor cells. These tools will allow us to directly determine the number of progenitors entering the thymus under conditions of health and disease, to separate entry into thymic tissue from early expansion phases, and to identify cellular and molecular feedback loops restricting progenitor entry. Furthermore, experiments proposed here will allow us to shed light on the highly controversial question, whether the thymic microenvironment is permissive for non-T cells to develop.Taken together, the proposed experiments will foster our understanding of the earliest events of T cell development under both, physiologic and pathophysiologic conditions, and, thus, point toward new directions of improving T cell reconstitution after HSCT.