Tolerance induction by thymic medullary epithelium.

To study the role of thymic medullary epithelium in tolerance induction, the third and fourth branchial clefts of embryos from E mu-Kb transgenic mice, which express the major histocompatibility complex class I antigen H-2Kb exclusively on medullary thymic epithelium, were grafted to athymic nude mice. The grafts differentiated into tissue that morphologically resembled normal thymus. These grafts expressed the H-2Kb antigen appropriately and gave rise to a functional T cell repertoire. In vivo tolerance to H-2Kb disparate skin grafts was invariably found in mice expressing H-2Kb in the medulla or in both medulla and cortex of C57BL/6 branchial cleft-grafted controls. In marked contrast, in vitro cytotoxicity assays demonstrated reactivity toward H-2Kb in the presence of interleukin 2, and limiting-dilution analyses showed similar frequencies of cytolytic T cell precursors reactive to H-2Kb and to third-party stimulators. Medullary epithelium can, therefore, induce split tolerance, in which in vivo tolerance is accompanied by strong in vitro responses in the presence of interleukin 2.