SUPPRESSOR T CELLS AND TOLERANCE TO MHC ANTIGENS

Tolerance to the major transplantation alloantlgens, coded by the major histocompatibility gene complex, is readily induced in newborn rats by the intravascular injection of bone marrow cells from immuno-competent allogeneic donors, usually F1 hybrids carrying one haplotype identical with that of the newborn strain. Analysis of the alloreactive repertoire of lymphocytes from adult tolerant animals of this provenance has shown that, not only are their cells unreactive in all in vivo and in vitro assays against the tolerated alloantigens but they actively and specifically suppress recovery of alloreactivity against these antigens on adoptive transfer to irradiated syngeneic animals. This suppression is mediated by a lymphocyte with the property of rapid recirculation from blood to lymph. These cells are not found in organs deficient in recirculating cells, such as thymus and bone marrow. Inocula of recirculating cells from tolerant donors have been treated with specific alloantisera and monoclonal antibodies to define the membrane antigen phenotype and receptor repertoire of suppressor cells. They are inactivated by treatment with alloantisera of specificity restricted to the unshared haplotype on chimaeric cells. Immunofluorescent studies have shown that chimaeric cells are present in very small numbers throughout the lymphoid tissues of tolerant rats and adoptive recipients of their cells. There is a clear correlation between survival of chimaeric cells and persistence of tolerance on transfer; however the chimaeric cell responsible for suppression is a highly differentiated functional subtype of T lymphocyte. The mode of action of these cells is unknown but for genetic reasons can be inferred to involve reactivity against the idiotypes on receptors for allo-antigen in the tolerant host. A model for self-sustaining chimaerism, suppression, clonal inactivation and tolerance which incorporates these findings is presented.