ESTABLISHMENT OF TISSUE-SPECIFIC TOLERANCE IS DRIVEN BY REGULATORY T-CELLS SELECTED BY THYMIC EPITHELIUM

Grafts of thymic epithelium (TE) rudiments restore T cell development and function in allogeneic athymic mice. These TE chimeras are specifi cally tolerant to grafts of peripheral tissues (e.g. skin and heart) f rom the TE donor strain, although they harbor peripheral immunocompete nt T cells capable of rejecting those grafts. Initial analysis has sho wn that TE chimeras also harbor TE-selected CD4 T lymphocytes that inh ibit graft rejection by tissue-reactive T cells in immunocompetent rec ipients. Peripheral tolerance in TE chimeras is thus maintained by dom inant mechanisms dependent on regulatory CD4 T lymphocytes. Here we sh ow that TE-selected regulatory T cells recruit nontolerant tissue-reac tive CD4 and CD8 T cells to express similar regulatory functions. Only recent thymic emigrants, but not peripheral resident mature T cells a re susceptible to this process of functional education, which also req uires exposure to specific antigens and occurs entirely in the periphe ry. We propose that these mechanisms play a major role in establishing and maintaining natural self tolerance to tissue-specific antigens.