Mathematical modelling of T cell homeostasis

T cell homeostasis describes the process through which the immune system regulates cell survival, proliferation, differentiation and death to maintain T cell numbers and diversity in a range of different conditions. The aim of this thesis is to better understand how this process leads to the development of the naive CD4+ T cell compartment during childhood. Mathematical modelling is used in combination with experimental observations to estimate naive T cell kinetics over the lifetime of an individual. The analysis described here shows that post-thymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved from birth to age 20 years; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens with age and the naive population is maintained by improved naive cell survival. Thymic output is quantified from birth to age 60 years by combining models to interpret naive T cell TRECs and Ki67 expression data. Three distinct phases of thymic T cell output are identified: (i) increasing production from birth to age 1 year; (ii) steep decline to age 8 years; (iii) slow decline from age 8 years onwards. Finally, the role of inter-cellular variation in T cell residency times is explored. It is able to explain the persistence of PTK7+ naive CD4+ T cells in thymectomised individuals. Importantly, the model predicts the accumulation of veteran PTK7+ T cells in older individuals and suggests that the residual population in thymectomised individuals will also consist predominantly of veteran PTK7+ T cells. The model has implications for the use of PTK7 as a marker of recent thymic emigration and also naturally explains improved T cell survival in older individuals.