Abstract
Cell proliferation is the common characteristic of all biological systems. The immune system insures the maintenance of body integrity on the basis of a continuous production of diversified T lymphocytes in the thymus. This involves processes of proliferation, differentiation, selection, death and migration of lymphocytes to peripheral tissues, where proliferation also occurs upon antigen recognition. Quantification of cell proliferation dynamics requires specific experimental methods and mathematical modelling. Here, we assess the impact of genetics and aging on the immune system by investigating the dynamics of proliferation of T lymphocytes across their differentiation through thymus and spleen in mice. Our investigation is based on single-cell multicolour flow cytometry analysis revealing the active incorporation of a thymidine analogue during S phase after pulse-chase-pulse experiments in vivo, versus cell DNA content. A generic mathematical model of state transition simulates through Ordinary Differential Equations (ODEs) the evolution of single cell behaviour during various durations of labelling. It allows us to fit our data, to deduce proliferation rates and estimate cell cycle durations in sub-populations. Our model is simple and flexible and is validated with other durations of pulse/chase experiments. Our results reveal that T cell proliferation is highly heterogeneous but with a specific “signature” that depends upon genetic origins, is specific to cell differentiation stages in thymus and spleen and is altered with age. In conclusion, our model allows us to infer proliferation rates and cell cycle phase durations from complex experimental 5-ethynyl-2'-deoxyuridine (EdU) data, revealing T cell proliferation heterogeneity and specific signatures.
Highlights
Cell division is a characteristic of biological systems, with variability of rates of proliferation and interphase duration according to the type of organism, organ, and period of life
We assess the impact of genetics and aging on immune system dynamics by investigating the dynamics of proliferation of T lymphocytes across their differentiation through thymus and spleen in mice
Modelling T cell proliferation in aging funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Summary
Cell division is a characteristic of biological systems, with variability of rates of proliferation and interphase duration according to the type of organism, organ, and period of life. There remain open questions concerning the rates of thymocyte production that result from various processes, such as differentiation, proliferation, selection, and death of T cells, and that influence the homeostasis and life-span of naïve and effector/memory T cells in secondary lymphoid organs. A number of studies have tried [15,16,17], often with the help of modelling [1, 18,19,20,21], to quantify thymocyte production, thymic output, and the processes involved in maintenance of a T lymphocyte dynamic equilibrium in the periphery in humans or mice [1, 22,23,24,25,26]. The flexibility of T cell behaviour has already been approached, in particular for peripheral cells [29], but references concerning quantitative proliferation are still lacking
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