DIRECT THYMIC INVOLVEMENT IN ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION - EVIDENCE FOR A NONDELETIONAL MECHANISM OF CENTRALLY INDUCED TOLERANCE TO EXTRATHYMIC ANTIGENS IN ADULT MICE

Recent reports have suggested that the dichotomy between central (thym ic) and peripheral T cell tolerance is not absolute and that self-tole rance in perinatal animals may also involve the intrathymic generation and release to the periphery of Ag-specific immunoregulatory T cells. We have expanded this concept to include tolerance to non self Ags ad ministered extrathymically to adult animals. In this study, we use the anterior chamber-associated immune deviation (ACAID) to demonstrate t hat central regulation of acquired peripheral tolerance can be induced in adult mice by the intraocular administration of low doses of nonse lf Ag. The results show that adult thymectomy prevents the inhibition of trinitrophenol (TNP)-specific delayed-type hypersensitivity, which normally occurs after injection of TNP-BSA into the anterior chamber ( AC) of the eye. Thymocytes obtained from mice 1 to 3 days, but not 5 t o 7 days, after AC injection of TNP-BSA or BSA alone specifically tran sfer inhibition of delayed-type hypersensitivity to mice primed with t he homologous Ag. The latter observation, when correlated with the tim e of onset of ACAID, suggests that immunoregulatory T cells are formed in the thymus within 24 h and are exported to the peripheral lymphoid tissues between 2 and 5 days after AC injection of Ag. Immunomagnetic separation of thymocytes revealed that the immunoregulatory activity resides within the minor subset of CD4(-), CD8(-), TCR-alpha beta(+) c ells, previously postulated to induce fas ligand-mediated apoptosis an d Th1 to Th2 immune deviation. Hence, the present study identifies ACA ID as a prototypical model of centrally induced, nondeletional toleran ce to extrathymic nonself Ags.