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

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.

Obstetric anal sphincter injury by maternal origin and length of residence: a nationwide cohort study

Objective: To estimate the association between maternal origin and obstetric anal sphincter injury (OASI), and assess if associations differed by length of residence. Design: Population-based cohort study. Setting: The Medical Birth Registry of Norway. Population: Primiparous women with vaginal livebirth of a singleton cephalic fetus between 2008 and 2017 (n = 188 658). Methods: Multivariable logistic regression models estimated adjusted odds ratios (aORs) for OASI with 95% CI by maternal region of origin and birthplace. We stratified models on length of residence and paternal birthplace. Main outcome measures: OASI. Results: Overall, 6373 cases of OASI were identified (3.4% of total cohort). Women from South Asia were most likely to experience OASI (6.2%; aOR 2.24, 95% CI 1.87–2.69), followed by those from Southeast Asia, East Asia & the Pacific (5.7%; 1.59, 1.37–1.83) and Sub-Saharan Africa (5.2%; 1.85, 1.55–2.20), compared with women originating from Norway. Among women born in the same region, those with short length of residence in Norway (0–4 years), showed the highest odds of OASI. Migrant women across most regions of origin had the lowest risk of OASI if they had a Norwegian partner. Conclusions: Primiparous women from Asian regions and Sub-Saharan Africa had up to two-fold risk of OASI, compared with women originating from Norway. Migrants with short residence and those with a foreign-born partner had higher risk of OASI, implying that some of the risk differential is due to sociocultural factors. Some migrants, especially new arrivals, may benefit from special attention during labour to reduce morbidity and achieve equitable outcomes

Obstetric anal sphincter injury by maternal origin and length of residence: a nationwide cohort study

Objective To estimate the association between maternal origin and obstetric anal sphincter injury (OASI), and assess if associations differed by length of residence. Design Population-based cohort study. Setting The Medical Birth Registry of Norway. Population Primiparous women with vaginal livebirth of a singleton cephalic fetus between 2008 and 2017 (n = 188 658). Methods Multivariable logistic regression models estimated adjusted odds ratios (aORs) for OASI with 95% CI by maternal region of origin and birthplace. We stratified models on length of residence and paternal birthplace. Main outcome measures OASI. Results Overall, 6373 cases of OASI were identified (3.4% of total cohort). Women from South Asia were most likely to experience OASI (6.2%; aOR 2.24, 95% CI 1.87–2.69), followed by those from Southeast Asia, East Asia & the Pacific (5.7%; 1.59, 1.37–1.83) and Sub-Saharan Africa (5.2%; 1.85, 1.55–2.20), compared with women originating from Norway. Among women born in the same region, those with short length of residence in Norway (0–4 years), showed the highest odds of OASI. Migrant women across most regions of origin had the lowest risk of OASI if they had a Norwegian partner. Conclusions Primiparous women from Asian regions and Sub-Saharan Africa had up to two-fold risk of OASI, compared with women originating from Norway. Migrants with short residence and those with a foreign-born partner had higher risk of OASI, implying that some of the risk differential is due to sociocultural factors. Some migrants, especially new arrivals, may benefit from special attention during labour to reduce morbidity and achieve equitable outcomes. Tweetable abstract Anal sphincter injury during birth is more common among Asian and Sub-Saharan migrants and particularly among recent arrivals