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

T细胞的发育是一个高度动态的过程，始于骨髓，但依赖于祖细胞向胸腺的迁移。胸腺是T细胞谱系承诺、T细胞受体(TCR)谱系形成和选择的场所，以防止无功能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。虽然在健康人中一般不是问题，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。预适应方案根除了患者的免疫系统，在退化的胸腺中只能从头产生少量的T细胞。因此，尤其是老年患者在HSCT后免疫缺乏期延长。因此，促进T细胞再生或使老化的胸腺恢复活力是改善HSCT预后的关键。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，我们最近量化了在胸腺定植的祖细胞的数量和这些祖细胞可获得的壁龛的数量。在这项提案中，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量化体外和体外的细胞周期动力学，并研究胸腺内增殖与关键发育程序的相互依赖。具体地说，我们将解决这些基本问题：在稳态和存在动态平衡压力的情况下，如何在细胞周期水平上调节组织动态平衡和种群大小？生理性T细胞前体细胞的异质性如何在数量上影响稳定状态和再生过程中的T细胞输出？在暴露于胸腺微环境的时间、细胞分裂数和T细胞谱系承诺之间，祖细胞之间的相互依赖是什么？回答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.