Learning from the thymic human cell atlas for T cell engineering

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One of the central questions in immunology is how adaptive immunity generates its diversity while maintaining tolerance. The keymediators of tolerance are T cells, which develop in the thymus, where thymocytes rearrange their T cell receptor genes and undergopositive 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 thedevelopmental 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 inimportance since several T cell types are now therapeutics in cancer and transplantation, raising the question of how to engineerspecific 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 imagingtechnologies. By combining multi-modal single cell genomics with multi-scale spatial genomics and imaging technologies, we willgenerate 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 predictlymphocyte 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 engineeringapproaches.This powerful integrated approach combines genomics, imaging and tissue engineering together with computational analyses todissect design principles of the thymus, a central organ of the immune system. This knowledge will guide the development ofengineered T cells as research reagents, and ultimately as therapeutics.