Mapping the early thymic progenitor niche

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Malignant diseases of the blood system, such as leukemias, can be successfully treated by hematopoietic stem cell transplantation (HSCT) following destruction of the patient's tumor cells but also his hematopoietic system. However, HSCT is frequently accompanied by a prolonged phase of immunodeficiency, which results in an increased danger of acute bacterial and fungal infections and reactivation of latent viruses. This phase of immunodeficiency is largely due to slow recovery of the adaptive immune system and T cells in particular. Therefore, it is critical to better understand the molecular and cellular mechanisms of T cell development and regeneration to devise strategies to improve T cell reconstitution after HSCT.T cell development occurs in the thymus, but this process is strictly dependent on the recruitment of progenitor cells from the bone marrow. We have previously characterized multiple progenitor cell populations that are able to enter the thymus and give rise to T cells. Furthermore, we have identified the chemokine receptors CCR7 and CCR9 as critical mediators of progenitor entry. Recruitment of progenitor cells to the thymus is tightly regulated, but molecular and cellular feedback mechanisms that restrict entry into the thymus remain poorly understood. Here, we plan to characterize the earliest phase of progenitor entry using a novel mouse model in combination with cellular bar coding to track the offspring of individual progenitor cells. These tools will allow us to directly determine the number of progenitors entering the thymus under conditions of health and disease, to separate entry into thymic tissue from early expansion phases, and to identify cellular and molecular feedback loops restricting progenitor entry. Furthermore, experiments proposed here will allow us to shed light on the highly controversial question, whether the thymic microenvironment is permissive for non-T cells to develop.Taken together, the proposed experiments will foster our understanding of the earliest events of T cell development under both, physiologic and pathophysiologic conditions, and, thus, point toward new directions of improving T cell reconstitution after HSCT.