T cells mature in the thymus, a small organ behind the breastbone, where they learn to attack foreign invaders without attacking the body's own tissues—and researchers are building a complete 3D map of that process at the level of individual cells and genes. The problem is that scientists still do not fully understand the molecular steps that guide a developing T cell through the thymus, or how the organ's physical structure shapes that journey. This matters because several types of T cells are now used as living drugs against cancer and in transplant medicine, but engineers cannot yet reliably produce specific T cell subtypes in the lab. This project will combine single-cell genomics, spatial imaging, and computational modelling to reconstruct the thymus's architecture in three dimensions. The team will then test their predictions using artificial thymus organoids—miniature lab-grown versions of the organ. If successful, the work will reveal design principles for engineering bespoke T cells on demand, turning fundamental knowledge about immune development into a practical toolkit for manufacturing therapeutic immune cells.
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One of the central questions in immunology is how adaptive immunity generates its diversity while maintaining tolerance. The key mediators of tolerance are T cells, which develop in the thymus, where thymocytes rearrange their T cell receptor genes and undergo positive and negative selection. This ensures their ability to recognise antigen in the context of MHC, whilst avoiding self-reactivity. We are still far from fully understanding the steps in these processes at the molecular level, especially in humans: What are the developmental trajectories of different T cell subtypes, and how do they relate to their journey through the organ during maturation? What is the functional role played by the macro- and micro-scale environments in regulating this? These questions have gained in importance since several T cell types are now therapeutics in cancer and transplantation, raising the question of how to engineer specific T cell subsets in vitro. In AIM 1, we propose to generate an organ-scale 3D thymic cell atlas at full genomic breadth through genomics and imaging technologies. By combining multi-modal single cell genomics with multi-scale spatial genomics and imaging technologies, we will generate a rich data set for deep and comprehensive reconstruction of tissue architectures in a thymic lobe. In AIM 2, we will carry out computational data integration with new methods for 3D multi-modal atlas assembly to predict lymphocyte developmental mechanisms at micro and macro scales. In AIM 3, we will use an artificial thymic organoid system to simultaneously validate our findings and enhance T cell engineering approaches. This powerful integrated approach combines genomics, imaging and tissue engineering together with computational analyses to dissect design principles of the thymus, a central organ of the immune system. This knowledge will guide the development of engineered T cells as research reagents, and ultimately as therapeutics.
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