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

T细胞发育是一个高度动态的过程，它始于骨髓，但取决于祖细胞向胸腺的迁移。胸腺是T细胞系定型、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，初始T细胞的产生随着年龄的增加而下降。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）后早期的主要潜在问题。预处理方案消除了患者的免疫系统，并且在退化的胸腺中只能重新产生少量的T细胞。因此，特别是老年患者在HSCT后遭受长期的免疫缺陷。因此，增强T细胞再生或使老化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。我们已经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，我们最近已经量化的数量的祖细胞定殖胸腺和数量的壁龛访问这样的祖细胞。在这个建议中，我们将解决胸腺内人口控制的关键问题。为此，我们已经开发了实验工具，在体外和体外定量细胞周期动力学，并调查胸腺内增殖的相互依赖性与关键的发展计划。具体来说，我们将解决这些基本问题：如何组织稳态和人口规模调节在细胞周期水平在稳态和稳态压力的存在下？生理性T细胞祖细胞的异质性如何定量地影响稳态和再生期间的T细胞输出？胸腺微环境暴露时间、细胞分裂次数和T细胞系定型之间祖细胞的相互依赖性是什么？解决这些基本问题可能为优化骨髓移植后T细胞再生铺平道路。

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.