Cell cycle dynamics during early T cell development and their role in tissue homeostasis.

早期 T 细胞发育过程中的细胞周期动力学及其在组织稳态中的作用。

• 批准号: 396099519
• 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: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/396099519?language=en
• 关键词: Cell; cycle; dynamics; during; early

T cell development is a highly dynamic process that commences in bone marrow, but depends on migration of progenitor cells to the thymus. The thymus is the site of T lineage commitment, T cell receptor (TCR) repertoire formation and selection to prevent the emergence of non-functional or autoreactive cells. Production of naive T cells declines with increasing age due to thymic involution. Although generally not a problem in healthy individuals, this decline is a major underlying problem early after hematopoietic stem cell transplantation (HSCT). Pre-conditioning regimens eradicate the immune system of patients, and only small numbers of T cells can be generated de novo in an involuted thymus. As a consequence, especially elderly patients suffer from a prolonged phase of immunodeficiency after HSCT. Enhancing T cell regeneration or rejuvenating the aging thymus is therefore paramount to improve the outcome of HSCT. In addition, dysregulation of the T cell developmental program frequently results in formation of T cell leukemia.We have set out to develop novel experimental approaches to determine quantitative parameters of T cell development. Thus, we have recently quantified the number of progenitors colonizing the thymus and the number of niches accessible to such progenitors. In this proposal we will address key questions of intrathymic population control. To this end, we have developed experimental tools to quantitate cell cycle dynamics in vitro and in vitro and to investigate the interdependence of intrathymic proliferation with key developmental programs. Specifically, we will address these fundamental questions: How is tissue homeostasis and population size regulated at the cell cycle level at steady state and in the presence of homeostatic pressure? How does heterogeneity of physiologic T cell progenitors quantitatively affect T cell output at steady state and during regeneration? What is the interdependence of progenitors between exposure time to the thymic microenvironment, number of cell divisions and T lineage commitment? Answering these fundamental questions may pave the way to optimizing T cell regeneration after BM transplantation.

T 细胞发育是一个从骨髓开始的高度动态的过程，但依赖于祖细胞向胸腺的迁移。胸腺是 T 谱系定型、T 细胞受体 (TCR) 库形成和选择的场所，以防止非功能性或自身反应性细胞的出现。由于胸腺退化，幼稚 T 细胞的产生随着年龄的增长而下降。虽然在健康个体中通常不是问题，但这种下降是造血干细胞移植 (HSCT) 后早期的一个主要潜在问题。预处理方案会根除患者的免疫系统，并且在退化的胸腺中只能重新生成少量的 T 细胞。因此，尤其是老年患者在 HSCT 后会遭受长期的免疫缺陷。因此，增强 T 细胞再生或使衰老的胸腺恢复活力对于改善 HSCT 的结果至关重要。此外，T 细胞发育程序的失调经常导致 T 细胞白血病的形成。我们已着手开发新的实验方法来确定 T 细胞发育的定量参数。因此，我们最近量化了定植于胸腺的祖细胞数量以及此类祖细胞可进入的生态位数量。在本提案中，我们将解决胸腺内种群控制的关键问题。为此，我们开发了实验工具来定量体外和体外细胞周期动力学，并研究胸腺内增殖与关键发育程序的相互依赖性。具体来说，我们将解决这些基本问题：在稳态和存在稳态压力的情况下，组织稳态和群体大小如何在细胞周期水平上受到调节？生理性 T 细胞祖细胞的异质性如何定量影响稳态和再生过程中 T 细胞的输出？祖细胞暴露于胸腺微环境的时间、细胞分裂次数和 T 谱系定型之间的相互依赖性是什么？回答这些基本问题可能为优化 BM 移植后 T 细胞再生铺平道路。