REGULATORY T-CELLS IN THYMIC EPITHELIUM-INDUCED TOLERANCE .1. SUPPRESSION OF MATURE PERIPHERAL NONTOLERANT T-CELLS

Athymic mice grafted at birth with allogeneic thymic epithelium (TE) d isplay life-long tolerance to tissue grafts of the TE donor strain, in spite of harboring peripheral T cells capable of rejecting those graf ts. Tolerance is maintained in these chimeras by TE-specific regulator y CD4 T cells. We presently address the quantification and the mechani sms of this dominant tolerance process. C57BL/6 mice containing variab ie but-defined numbers of peripheral, resident T cells received cell t ransfers of graded numbers of peripheral T cells from B6(BALB E10) chi meras (C57BL/6 nude mice grafted with TE from 10-day-old BALB/c embryo s), resulting in a series of animals containing a wide range of donor (tolerant) versus host (non-tolerant)T cell chimerism. Increasing the relative repre sentation of donor T cells results in a progressive del ay in the rejection of BALB/c skin grafts, life-long tolerance being a chieved at a ratio of tolerant and non-tolerant T cell populations of 1. In recipients displaying full tolerance, graft-reactive non-toleran t T cells were not deleted, anergized or committed to noninflammatory functions. Thus, sorted host T cells from tolerant recipients readily rejected BALB/c skin grafts upon transfer to immunodeficient animals. Finally, measurements of ''helper'' and inflammatory activities, as we ll as interleukin-4 and interferon-gamma production, failed to discrim inate between T cell populations from tolerant and non-tolerant animal s after specific in vitvo stimulation. We conclude that: (a) TE-select ed regulatory T cells can suppress, in a quantitative manner, in vivo T cell responses against major and minor histocompatibility antigens e xpressed by the TE and, (b) this suppressive activity neither inactiva tes mature non-tolerant T cells, nor does it seem to drive their diffe rentiation along noninflammatory pathways.