Engineering a Functional Synthetic Thymus (360G-Wellcome-211944_Z_18_Z)

T-cells, the central executors of adaptive immunity, are generated in the thymus. Thymus biology is intricate, reflecting the complex processes that control its seeding with haematopoietic progenitors, and subsequent T-cell commitment, differentiation and repertoire selection. Physiological T-cell repertoire development and selection is not yet possible outside the native organ. Recent advances, including the advent of T-cell immunotherapy, have brought thymus biology into the spotlight, and the capacity to recapitulate and control thymus function would open enormous possibilities for novel immune-mediated therapies for cancer, inflammation, immunodeficiency and autoimmunity. Our collaborative aim is thus to create a fully functional, synthetic, thymus organoid, as a tractable enabling system for basic research and a therapeutic source of functional T-cells. To achieve this, we will decipher the molecular and cellular mechanisms that control development and function of the epithelial cell compartment of the thymic stroma which provides the organ’s specialist functions by integrating cutting-edge stem cell biology with biomaterials engineering, single cell time-and-space-controlled transcriptomic interrogation and advanced mathematics. The project outputs will be transformative for understanding the synthetic formation of a primary lymphoid organ and for studies of T-cell maturation with its translational potential for new immunotherapeutics including thymus replacement or regeneration.