Preview

PDF, English Download (3MB) | Terms of use

Abstract

Regulatory T (Treg) cells are generated in the thymus and are involved in the regulation of self-tolerance, immune homeostasis and immune responses. So far the mechanisms behind the Treg cell differentiation and their function are not fully understood. The work of this thesis aimed to gain insight into these processes. We used a quantitative differential proteomics approach and identified 164 proteins that were differentially expressed in Treg cells compared to conventional T cells. Among these transcription factor 7 (TCF7) was identified as a promising candidate for further investigations of its role in Treg cells. Using a Tcf7-deficient mouse model we observed elevated frequencies of Treg cells among CD4 single-positive and CD4 CD8 double-positive thymocytes in the absence of TCF7. Quite surprisingly, we also found a fraction of CD4 CD8 double-negative cells that expressed the Treg cell transcription factor forkhead box P3 (FOXP3) independent of previous T cell receptor engagement, indicating that TCF7 prevents premature FOXP3 expression. In vitro Treg precursor differentiation assays showed that the reduction of TCF7 levels was beneficial for the Treg cell generation capacity and that TCF7 activation through the β catenin/Wnt pathway had the opposite effect. Furthermore, our results indicated that FOXP3 supports down regulation of TCF7, as FOXP3 expression in thymocytes was accompanied by decreased levels of TCF7 and enforced expression of FOXP3 in T cells caused reduced expression levels of TCF7. In addition to its role in thymic Treg cell differentiation, we found that TCF7 was involved in regulating the balance between Treg and TH17 cells and the survival of NKT cells. TCF7 deficiency also changed the typical expression patterns of Treg and T cell markers. In summary, we propose that TCF7 is involved in limiting the access into the Treg cell lineage and that TCF7 influences peripheral T cell subsets.