MECHANISMS OF IMMUNE TOLERANCE INDUCTION THROUGH THE THYMIC - EXPRESSION OF A PERIPHERAL TISSUE-SPECIFIC PROTEIN

A major process through which the immune system becomes tolerant to se lf proteins involves the deletion of self reactive cells in the thymus , However, T cells reactive to peripheral tissue-specific proteins can escape this deletion and become tolerized in the periphery by a varie ty of mechanisms, We report here, contrary to expectation, that the pa ncreas-specific protein, elastase I, is also expressed at a low level in the thymus, and that this thymic expression contributes to toleranc e induction, To study the mechanism of this tolerance induction, we ut ilized a double transgenic mouse model, In these mice the expression o f a model protein, SV40 T antigen, is directed by the elastase I promo ter and hence parallels elastase I expression in the pancreas and thym us, These mice were crossed with mice transgenic for a TCR specific fo r T antigen, so the majority of thymocytes and T cells in these mice e xpress the transgene, In double transgenic mice we find that thymic ex pression of T antigen results in anergic thymocytes which also show a reduction of T(h)1 activity with no decrease in T(h)2 activity, These functional characteristics persist in peripheral T cells, but there is also a depletion in the number of T antigen reactive T cells in lymph nodes, Chimeras were constructed which directly demonstrated that the thymus is the site of tolerance induction and that the tolerizing ele ment is thymic epithelium. We propose that the loss of T(h)1 activity as a consequence of the thymic epithelium being encountered by tissue- specific proteins results in the functional tolerization of CTL in viv o, despite the fact that CTL are fully functional in vitro, In this wa y autoimmune destruction is contained, Thymic expression of peripheral proteins may therefore be an additional way in which tolerance to per ipheral proteins can be achieved.