Mechanism for the tolerance against thymic self

초록

Mechanism for the tolerance against thymic self T cell tolerance is established when the T cells develop to avoid harmful reactivity against self antigens expressed in thymus. In the periphery, organ specific tolerance can be established by various other mechanisms including anergy, ignorance, and regulatory T cells. Furthermore, antigen-presenting cells lacking costimulatory molecules in peripheral tissues initiate abortive immune responses. In order to further characterize tolerance to a thymic epithelial cell specific antigen, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT) expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical markers as well as costimulatory molecules and MHCII. When examining endogenous responses directed against LacZ, we observed significant tolerance. This tolerance was independent of Autoimmune Regulatory Element gene. When TDLacZ mice were crossed to CD4 TCR transgenic mouse reactive to LacZ, there was a complete deletion of DP thymocytes. Fetal thymic reaggregate culture of thymic stromal cells from TDLacZ and sorted thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells.