Bone marrow transplantation induces either clonal deletion or infectious tolerance depending on the dose

The concept of immunologic tolerance arose from bone marrow transplantation in neonatal or irradiated mice, in which the predominant mechanism is clonal deletion of donor-specific T cells by donor hemopoietic cells in the recipient thymus. A short term treatment with nonlytic CD4 and CD8 mAbs can induce tolerance to tissue allografts or reversal of spontaneous autoimmunity. Such tolerance to skin or heart allografts is dependent on "infectious" tolerance mediated by regulatory CD4+ T cells. We show here, for multiple minor Ag differences, that while a large inoculum of donor marrow produces significant deletion of Ag-reactive cells as expected, a low marrow dose generates tolerance with little evidence of clonal deletion. Only this low dose tolerance can be transferred to unmanipulated recipients via CD4+ T cells, can be passed onto naive T cells as if infectious, and can act to suppress rejection of third party Ags when "linked" on F1 grafts.