Aspects of T cell development contributing to autoimmunity

Abstract: Autoimmunity, such as type 1 diabetes (T1D), arises as a result of tolerance breakdown against host tissues, i.e. the ?-cells. Central tolerance is established during thymic T cell development and defects in key events during this process could contribute to the pathogenesis of autoimmune diseases. The work presented in this thesis was aiming at unravelling some of those aspects. We have investigated the impact of thymic expression of TGF-? and insulin on T cell development as well as elicudated the molecular basis for the apoptosis resistance in the non-obese diabetic (NOD) mouse. The role of thymic expression of TGF-? was dissected by using TGF-? type II receptor cre/lox conditional knock out mouse model. By transplanting bone marrow to irradiated recipients we restricted the phenotype to hematopoietic stem cells. These mice develop a lymphoproliferative degenerating disease 6 to 9 weeks after bone marrow transfer. Our analysis revealed no difference in thymocyte distribution or apoptosis induction indicating that TGF-? is dispensable in these aspects. We did however observe increased proliferation of CD8+ thymocytes which might contribute to the immune defect in these animals. The impact of thymic insulin expression on development and selection of thymocytes was investigated by using insulin deficient fetal thymi. Analysis by fetal thymic organ cultures suggested that lack of insulin does not affect thymocyte differentiation. Furthermore, by transplanting insulin deficient fetal thymi under the kidney capsule of nude mice we were able to demonstrate that insulin can be re-expressed in the thymus by influx of bone marrow derived cells. This process might contribute to clonal deletion of insulin-reactive T cells. The NOD mouse displays thymocytes apoptosis resistance, which could also contribute to impaired negative selection and contribute to the development of type 1 diabetes. By analysing the expression of key proteins involved in apoptosis and cell cycle signalling we were able to demonstrate that defective up-regulation of p53 and caspases-1 and 11 are linked to this trait. In summary, the results presented in this thesis depict factors capable of affecting T cell development and establishment of tolerance, which ultimately might contribute to development of autoimmune disorders such as T1D.