Glucocorticoids in the development and homeostasis of T lymphocytes

Sammanfattning: Until recently the fact that glucocorticoids (M) play an essential physiological role in regulation of the immune system in health and disease was not fully appreciated. The main aims of this thesis were to investigate the effects of physiological nonstressed levels of endogenous GCs on the development, differentiation and homeostasis of T lymphocytes. The thymus has endocrine features. It expresses some mediators of the HPA axis such as ACTH and CRH. Our previous studies suggest that the thymus could produce GCs. Thus, in paper I we investigated this issue. Our results demonstrated that thymic epithelial cells (TEC) contain enzymes required for GC synthesis and these cells were able to produce a GC activity. This was based on the observation that TEC could activate, in a paracrine fashion, a GR- dependent reporter gene in cocultured reporter cells. The TEC-derived GCs could induce apoptosis in the thymocytes in a coculture system, suggesting that they might play a physiological role in the development of thymocytes. Previous studies have shown that the T cell receptor (TCR) and GC signaling demonstrate cross communication, mutually influencing each other's signal transduction pathways. Thus, we became interested in investigating the effects of TCR signaling on the GC signaling in vivo (paper II). Taking advantage of a TCR transgenic mice system, in which a majority of the thymocytes express a functional TCR transgene, we were able to show that thymocytes from these mice were relatively resistant to GC-induced apoptosis. This was likely due to decreased expression of GR and increased NF-kappaB activity (paper II). Our results also demonstrated a physical interaction between the GR and NF-kappaB proteins in thymocytes. The results suggest that TCR signaling inhibits GC signaling in thymocytes. Our previous studies demonstrated that thymic apoptosis was decreased in these TCR transgenic mice. Thus, we suggest that GCs have an apoptotic effect on thymocytes and this could be inhibited by TCR signaling in vivo. The regulatory effects of physiological non-stressed levels of endogenous GCs on thymocytes and T cells are not completely known. Furthermore, it is not clear how much of the GC effects are through directly affecting these cells. To understand the direct effects of basal levels of endogenous GCs on the development and homeostasis of T cells, we generated transgenic mice with altered GC sensitivity restricted to the thymocytes and peripheral T cells (paper III and paper IV). Our results demonstrated that endogenous GCs exert suppressive effects on the thymocytes in young mice (paper III), and protective effects on these cells in aged mice (paper IV). Endogenous GCs, however, exert suppressive effects on the number of peripheral T cells in both young and aged mice. In addition, these suppressive effects were more pronounced on CD4+ T cells, resulting in a decreased CD4+:CD8+ T cell ratio. Taken together, our results demonstrate that endogenous GCs at physiological non-stressed levels significantly influence the development, differentiation and homeostasis of T cells.