ORGANise-T · Dissecting the body-wide spatio-temporal organisation of human resident T helper cells

T helper cells represent a heterogeneous population of immune cells that are critical for host defense and, if dysregulated, for pathologies such as autoimmunity and allergy. T cell responses take place in peripheral tissues. Yet, insights into their identity and regulation stem almost exclusively from investigations of circulating blood, which comprises only 2% of the total human T cell population. Accordingly, current immunomodulatory drugs act systemically, but lack tissue specificity. Despite progress in the temporary suppression of chronic inflammatory diseases, they still fail to be curative. This project aims to address this unmet medical need by generating fundamental insights into the dynamic compartmentalisation of human tissue resident T helper cells across space and time.I have established a surgical patient cohort for the collection of multi-organ tissue samples and a cohort of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that enables tracking T cell tissue entry and exit over time in matched organs by single-cell chimerism analysis. Using multimodal state-of-the-art technologies and specialised high-throughput cell culture methodologies in these two unique patient cohorts, the project will dissect 1) the phenotypic, functional and transcriptional identity and molecular regulation of human resident T helper cells across tissues, 2) the compartmentalisation of their antigen specificities across tissues, 3) the dynamics of tissue entry, persistence and exit for distinct T helper cell types in space and time, and will then 4) exploit chimeric host/donor T cell-tracking to gain novel insights into the cellular and molecular pathways underlying graft-versus-host disease. Overall, ORGANise-T will establish first-of-its-kind insights into the spatio-temporal dynamic organisation of human T cell immunity in tissues. This will bring the next generation of immunotherapies to the level of tissue specificity.