Human thymus biology: insights from investigating inborn errors of immunity (360G-Wellcome-323586_Z_24_Z)

The thymus is a primary lymphoid organ where functional, self-tolerant T-lymphocytes mature through processes of positive and negative selection, requiring complex lympho-stromal crosstalk. Access to human thymus tissue is restricted, and the scope of current thymic organoid models is limited by the use of murine stromal cells. To maximise insights into T-lymphopoiesis and immune tolerance induction, I am developing novel human thymic organoids (hTO), using human thymic epithelial cells (TEC), with superior physiological and clinical relevance. Rare and more common thymic inborn errors of immunity will be characterised through the study of the impact of patient variants in known and novel candidate disease-causing genes on proteins, cells, and systems in these hTO. Using cutting-edge technologies, I aim to elucidate mechanisms underpinning thymic stroma maintenance and regeneration by identifying significant -and potentially druggable- pathways regulating TEC development and plasticity in healthy and diseased thymus, and in thymic allografts from athymic patients treated with thymus transplantation using cultured donor tissue. By maximising the power of multi-scale and multi- disciplinary approaches, I aspire to contribute to discovery science of human thymus biology and associated therapeutic advances in thymus function replacement and maintenance, with the potential to address a wider range of immune-related disorders.