Modelling T cell proliferation: Dynamics heterogeneity depending on cell differentiation, age, and genetic background

Area of Science:

• Immunology
• Cell Biology
• Systems Biology
• Computational Biology

Background:

• Cell proliferation is fundamental to biological systems, including the immune system's maintenance of body integrity.
• The immune system relies on continuous T lymphocyte production, differentiation, selection, death, and migration, with proliferation occurring in both thymus and peripheral tissues.
• Quantifying T lymphocyte proliferation dynamics requires specialized experimental methods and mathematical modeling.

Purpose of the Study:

• To assess the impact of genetics and aging on T lymphocyte proliferation dynamics.
• To investigate T cell proliferation across differentiation stages in the thymus and spleen of mice.
• To develop and validate a mathematical model for inferring proliferation rates and cell cycle durations.

Main Methods:

• Single-cell multicolour flow cytometry analysis using pulse-chase-pulse experiments in vivo.
• Incorporation of a thymidine analogue (5-ethynyl-2'-deoxyuridine, EdU) during the S phase, assessed against cell DNA content.
• A generic mathematical model of state transition using Ordinary Differential Equations (ODEs) to simulate cell behavior and fit experimental data.

Main Results:

• T cell proliferation is highly heterogeneous, exhibiting a distinct 'signature'.
• This proliferation signature is dependent on genetic origins and specific to T cell differentiation stages within the thymus and spleen.
• T cell proliferation dynamics are altered with age.

Conclusions:

• The developed mathematical model effectively infers proliferation rates and cell cycle phase durations from complex EdU labeling data.
• The study reveals significant heterogeneity in T cell proliferation, influenced by genetic background and age.
• Specific proliferation signatures exist for T cells at different differentiation stages in the thymus and spleen.