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

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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.