Tolerance induction against a tumor antigen by thymic epithelial compartments

초록

Central tolerance for T cells is established in the thymus while thymocytes are developing. Hematopoetic dendritic cells resent in the areas of the thymic corticomedullary junction are responsible for general tolerance induction, but tolerance to the tissue specific antigens are believed to be induced by Autoimmune regulatory element (AIRE) in the medullary thymic epithelial cells. However, tolerance against the antigen specific to the thymic cortical epithelial cells are established by the direct presentation of thymic cortical epithelial cells in AIRE independent mechanism. We previously showed these results using LacZ as a model soluble protein antigen specifically expressed in the thymic cortical epithelial cells using LacZ reporter. In order to understand the mechanisms of establishment and/or break of tolerance against autologous tumor antigens, we utilized the transgenic mouse lines expressing Enhaced Green Fluorescent Protein (EGFP) in the specific thymic compartment. The mouse lines were established using a promotor derived from the thymic epithelial specific gene, Thymic Stromal Cotransporter (TSCOT). Although endogenous TSCOT promotor is active mostly in the cortex, 3.1 Kb TSCOT promotor drives the reporter expression in the medulla (3.1T-EGFP, 3.1T-NTR-EGFP) while 9.1 Kb in the cortex (9.1T-NTR-EGFP). B16 melanoma cells stably expressing EGFP were introduced subcutaneously into C56Bl/6, 3.1T-EGFP, 3.1T-NTR-EGFP, and 9.1T-NTR-EGFP mouse lines and tolerance was measured by the response to EGFP as antigen. The results showed tolerance of EGFP specific CD4 T cells was evident in the 3.1T-EGFP and 9.1T-NTR-EGFP, indicating that tolerance to tumor specific EGFP was established by the medullary as well as cortical epithelial cells.