Investigating the relationship between regulatory T-cell depletion, behaviour and neuropsychiatric disorder risk: a multidisciplinary cross-species approach.

Shepherd, Freya 2025. Investigating the relationship between regulatory T-cell depletion, behaviour and neuropsychiatric disorder risk: a multidisciplinary cross-species approach. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Regulatory T cells are a critical subset of immune cells, comprising around 5% of circulating lymphocytes. Their reduction has been linked to immune disturbances— including altered cytokine profiles and increased inflammation—implicated in psychiatric conditions such as anxiety, depression, and psychosis. However, the direction and mechanisms of these associations remain unclear. This project investigates the behavioural and neuroimmune consequences of Treg depletion in rodent models and explores translational relevance through human genetic data. Chapter 3 establishes and validates a diphtheria toxin injection protocol using the FoxP3-DTR mouse model to achieve substantial Treg depletion. The chosen protocol balances eMective Treg reduction with minimal adverse health eMects, enabling behavioural assessments. Chapter 4 evaluates the behavioural consequences of Treg depletion in mice across a comprehensive battery of tests relevant to psychiatric phenotypes. Results show a significant increase in certain anxiety-like behaviours following Treg reduction. Chapter 5 assesses the specificity of these eMects across diMerent anxiety paradigms and examines stress physiology and inflammation. Anxiety-like behaviour was reliably, specifically observed in the elevated plus maze in DT-treated mice, and these mice displayed elevated baseline corticosterone and a blunted response to acute stress, suggesting a link between Tregs and hypothalamic-pituitary-adrenal axis regulation. Chapter 6 translates these findings to humans using a novel polygenic score based on Treg-sensitive, brain-expressed genes identified using the model described above. While its predictive power was limited, exploratory analyses indicated this score may better predict psychiatric traits, including anxiety-related features, than conventional or general immune polygenic scores—suggesting some biological specificity consistent with the rodent data. This thesis presents a novel integration of Treg-depletion models and biologically informed genetic tools to probe the link between immune dysregulation and psychiatric outcomes. Overall, findings support a role for Treg reduction in anxiety-like behaviour and stress regulation, oMering a foundation for future translational research into immune contributions to psychiatric conditions.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	25 July 2025
Last Modified:	25 Jul 2025 15:55
URI:	https://orca.cardiff.ac.uk/id/eprint/180045

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