The role of early growth response gene 1 in thymus cellularity regulation and recent thymic emigrant survival

The maintenance of a diverse repertoire of T cells is crucial for an efficient adaptive immune response. It is thought that the continuous output of new T cells from the thymus contributes to this diversity. The main goal of this dissertation is to investigate the function of a transcriptional regulator, early growth response gene 1 (Egr1), in the preservation of normal thymopoiesis and T cell homeostasis.; The maintenance of thymus size is dependent on the continual recruitment of progenitors from the BM into the thymus. It is unknown whether thymic cellularity feeds back to control the recruitment, survival or proliferation of these early thymic progenitors. We have previously shown that mice lacking Egr1 have increased thymic cellularity. We now show that Egr1 plays a role in controlling the recruitment of progenitors into the thymus through an intercellular signaling pathway. Egr1-deficient mice have increased frequencies of the earliest T lineage progenitors (ETP). However, the loss of Egr1 does not allow for increased survival or proliferation of ETP. It appears the loss of Egr1 leads to increased levels of P-selectin on thymic endothelial cells. The data suggest a model where Egr1 is involved in a negative feedback loop where resident CD4-CD8-double-negative (DN) cells control the recruitment of progenitors into the thymus through the regulation of thymic endothelial P-selectin expression.; It has been proposed that similar TCR signals are required for both positive selection and T cell homeostasis. Our lab has shown a role for Egr1 in efficient positive selection. We therefore investigated the role of Egr1 in regulating T cell homeostasis. We found that Egr1-deficient mice on TCR transgenic backgrounds have reduced numbers of peripheral T cells. The reduced numbers of naive T cells in Egr1-deficient TCR-transgenic mice can be traced back to reduced accumulation of recent thymic emigrants (RTE) in the periphery. The poor accumulation of RTE stems from increased apoptosis rates amongst mature single-positive thymocytes and recently emigrated cells. These data lead us to conclude that an Egr1-mediated signal is required for not only efficient positive selection, but also for the long-term survival of recently emigrated thymocytes.