Immune deficiency is becoming a more common clinical problem that will require novel strategies for therapy. This is an issue in the treatment of HIV-infected patients, and in patients that undergo bone marrow transplantation (BMT) to treat hematologic malignancies. In these cases, T cell deficiencies can lead to a high risk of opportunistic infection. Complete reconstitution of immune function requires restoration of the T cell compartment through output of new T cells from the thymus, and robust thymic output of new naive T cells requires rapid attainment of a large thymic cellularity. However, the mechanisms that control thymic cellularity have not been defined. We propose a novel mechanism that controls the size of the thymus in young adult mice. For thymus sizes normally seen in these animals, we hypothesize that the importation of new progenitors into the thymus from the blood is a limiting factor for thymus cellularity, and that there is negative feedback from DN thymocytes to limit importation. This negative feedback sets the homeostatic size of the thymus in young animals. In preliminary studies, we have found that mice deficient in the zinc finger transcription factor early growth response gene 1 (Egr1) have thymuses that are twice as large as thymuses in normal mice. Our studies suggest that Egr1 expression in thymocytes can limit the size of the earliest progenitor population in the thymus. Egr1 does not seem to have an intrinsic effect on progenitors as cells lacking Egr1 can increase the number of both Egr1-deficient and wild type progenitors in mixed radiation BM chimeras. In addition, we have found that p-selectin expression is increased in thymuses that are Egr1-deficient. As expression of p-selectin on the thymic endothelium has been shown to play a role in importation of progenitors into the thymus, we hypothesize that thymocytes provide Egr1- dependent negative feedback to the thymic endothelium to limit the entry of new progenitors into the thymus from the blood. This will be tested by (1) directly determining whether Egr1 expression in CD4/CD8 double negative thymocytes inhibits entry of progenitors into the thymus, and (2) determining if the increases in early thymocyte progenitor number and thymus cellularity that result from Egr1-deficiency are mediated by increased p-selectin expression. ? ? Project Narrative: Many patients currently suffer from induced immune system deficiencies that make them subject to a variety of infections. In these cases, new T cells must be generated by the thymus to develop effective immunity. This study explores the regulation of thymus size so that it might be possible to enhance thymus function after induced immune deficiency. ? ? ?
