High-resolution mapping of cell cycle dynamics during steady-state T cell development and regeneration in vivo

Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known about how stage-specific alterations in cell cycle behavior drive proliferation dynamics during T cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with the determination of DNA replication over time as well as fluorescent ubiquitination-based cell cycle indicator mice to establish a quantitative high-resolution map of cell cycle kinetics of thymocytes. We developed an agent-based mathematical model of T cell developmental dynamics. To generate the capacity for proliferative bursts, cell cycle acceleration followed a “stretch model” characterized by the simultaneous and proportional contraction of both G1 and S phases. Analysis of cell cycle phase dynamics during regeneration showed tailored adjustments of cell cycle phase dynamics. Taken together, our results highlight intrathymic cell cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T cell developmental program. [Display omitted] •A framework to quantitatively determine cell cycle phase duration in vivo•A stretch model explains steady-state thymocyte cell cycle speed transitions•Thymocyte cell cycle phase progression is heterogeneous•Cell cycle re-entry and G1 shortening promote thymus regeneration Kunze-Schumacher et al. have developed an experimental and computational framework to generate a quantitative high-resolution map of cell cycle phase durations during murine T cell development. This map provides insight into how cell cycle phases are adjusted between slow- and fast-dividing populations at steady state and in a preclinical model of thymus regeneration.