Uku Haljasorg defend his PhD on August 29th 2017

„Transcriptional mechanisms in thymic central tolerance“

professor Pärt Peterson, PhD (University of Tartu, Institute of Biomedicine and Translational Medicine),
Senior Research Fellow Martti Laan, PhD (University of Tartu, Institute of Biomedicine and Translational Medicine).

dr Jakub Abramson, PhD, (Department of Immunology, Weizmann Institute of Science, Iisrael)

A functional immune system is capable of reacting to antigens from invading pathogens (non-self) and maintaining immune tolerance towards autologous (self) and beneficial or benign foreign antigens. Immune tolerance is divided into central or peripheral tolerance depending on the time and site of induction. One of the two sites for central tolerance induction is an organ called thymus, where maturating T cells are taught to avoid reaction to self-antigens. The maturation of all T cells depends on thymic stromal cells, especially thymic epithelial cells that express a protein called Autoimmune Regulator (Aire). Aire regulates the expression of genes that help to eliminate T cells that consider self to be non-self. Mutations in the gene responsible for Aire protein are sufficient to cause a complex autoimmune syndrome affecting multiple organs in the body. Characterizing the mechanisms by which thymic transcription factors induce tolerance helps us to understand conditions such as autoimmune diseases and spontaneous abortions where the immune system is incapable of differentiating between self and non-self
The current thesis concentrates on transcriptional processes in thymic stromal cells that enforce central tolerance and therefore immune system as a whole. We identified an intergenic region critical for the expression of Aire in thymic epithelial cells. We also found pregnancy to affect the numbers and gene expression profiles of thymic stromal cells in a way which renders these cells suboptimal in attracting T cell progenitors into the thymus and directing their maturation. In the last part of the thesis we identified a transcription factor Irf4 to be one of first factors besides Aire that regulates T cell tolerance in the thymic epithelium.