Brain-resident regulatory T cells (brain Tregs) are potent anti-inflammatory cells capable of driving neuro-protection and neuro-repair across multiple inflammatory and degenerative conditions. The cells have a high therapeutic potential, with the key unknown limiting the clinical exploitation of brain Tregs being the unknown antigenic targets recognised by these cells. The technology and knowledge-base required for identifying the target antigens for T cell receptors (TCRs) are being rapidly developed, although few studies look at the self-reactive Treg population. Recent advances by the applicant groups have enabled these approaches to be scale-able, allowing for the first time the ambition to identify the antigens of an entire T cell repertoire to be imaginable. The small size of the murine brain Treg population, among the smallest tissue T cell population, combined with the proposed iterative multiplexed approaches, make the repertoire-level identification aim feasible for the first time. We can further validate homologous antigen targets in human patients, using cerebral spinal fluid samples and cutting-edge antigen- led screening. This project will give key insights to the nature of the Treg TCR repertoire, potentiate brain Treg exploitation, and unlock repertoire- scale TCR target identification for the broader field.

Major histocompatibility complex-1 (MHC-1) antigen presentation is required for T cell activation and cancer cell recognition. Triple negative breast cancer (TNBC) is a highly invasive breast cancer subtype whereby immunogenicity, as reflected by tumour-infiltrating T cells, is strongly associated with patient outcome. I have found that RASAL2-overexpressing cells have low MHC-1-related genes, suggesting an unexplored link between the RAS- GAP and MHC-1/TAP1/IFNGR1 axis. Given that MHC-1 expression is vital for CD8+ T cell activation and cytolytic ability, I hypothesise that RASAL2 downregulates MHC-1 in TNBC to suppress CD8+ T cell activity. This project will investigate the molecular mechanisms of RASAL2/MHC-1/TAP1/IFNGR1 axis regulation and assess the effect of this downregulation on cytotoxic CD8+ T cell effector function. Mass-spectrometry will be used to perform unbiased mapping of RASAL2-protein binding partners that are potentially associated with the immunosuppressive phenotype. Top hits will be validated with co- immunoprecipitation and gain/loss-of-function experiments to assess modulation of the axis. To investigate CD8+ T cell effector function, a TNBC-T cell co- culture system will be established in vitro and validated with 3D spheroids and patient-derived organoids. Furthermore, an immunocompetent TNBC syngeneic mouse model will be utilised to confirm this phenotype in vivo.

Prescription drugs are widely used in pregnancy, particularly to manage chronic conditions. However, since randomised clinical trials exclude pregnant people as standard practice, very few medicines are licensed to be used during pregnancy. Autoimmune conditions often affect female patients during their potentially reproductive years. My research will focus on drugs used to treat these conditions, and particularly on drugs called monoclonal antibody biologics. I aim to understand the safety of these drugs for both the patient and fetus, and how effectively they can treat autoimmune conditions during pregnancy. First, I will use genetic variants which mimic the effects of drugs by affecting protein levels in the blood. I will test how common and rare genetic variants affect patient's outcomes in pregnancy. Second, I will look at electronic health records to compare outcomes of comparable patients with differing drug regimens during their pregnancy. Finally, I will triangulate across these different methods and summarise my findings, in order to provide further information to inform clinician's decisions.