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Mapping the early thymic progenitor niche

绘制早期胸腺祖细胞生态位

基本信息

批准号：
243255185
负责人：
Professor Dr. Andreas Krueger
金额：
--
依托单位：
Professur für Molekulare Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/243255185?language=en
关键词：
Mapping early thymic progenitor niche

项目摘要

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.

血液系统的恶性疾病，如白血病，可以在摧毁患者的肿瘤细胞和造血系统后，通过造血干细胞移植(HSCT)成功地治疗。然而，HSCT经常伴随着免疫缺陷的延长阶段，这会导致急性细菌和真菌感染以及潜伏病毒重新激活的危险增加。免疫缺陷的这一阶段在很大程度上是由于适应性免疫系统恢复缓慢，特别是T细胞。因此，更好地了解T细胞发育和再生的分子和细胞机制，以制定策略促进HSCT后T细胞的重建是至关重要的。T细胞的发育发生在胸腺，但这一过程严格依赖于从骨髓中招募祖细胞。我们之前已经确定了能够进入胸腺并产生T细胞的多个祖细胞群体。此外，我们还发现趋化因子受体CCR7和CCR9是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，来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的数量，将进入胸腺组织与早期扩张阶段分开，并识别限制祖细胞进入的细胞和分子反馈回路。此外，这里提出的实验将使我们能够阐明一个备受争议的问题，即胸腺微环境是否允许非T细胞发育。综上所述，建议的实验将有助于我们理解生理和病理生理条件下T细胞发育的最早事件，从而为促进HSCT后T细胞重建指明新的方向。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors.

有限的生态位可用性抑制小鼠胸腺内树突状细胞从非定型祖细胞的发育

DOI：
10.1182/blood-2014-07-592667
发表时间：
2015
期刊：
Blood
影响因子：
20.3
作者：
Łyszkiewicz M;Ziętara N;Föhse L;Puchałka J;Diestelhorst J;Witzlau J;Prinz I;Schambach A;Krueger A
通讯作者：
Krueger A

Thymus Colonization: Who, How, How Many?