INDUCTION OF PERIPHERAL TOLERANCE TO CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) ALLOANTIGENS IN ADULT MICE - TRANSFUSED CLASS-I MHC-INCOMPATIBLE SPLENOCYTES VETO CLONAL RESPONSES OF ANTIGEN-REACTIVE LYT-2+ T-CELLS

The efficacy and the mode ofaction of pretransplant transfusion with class I major histocompatibility complex (MHC)-disparate splenocytes in establishing a state of peripheral tolerance in adult mice is analyzed. Adult mice injected intravenously with a critical number of ~5 x 107 allogenic splenocytes accept skin grafts and develop chimerism in the peripheral lymphatic tissues, but not in thymus and bone marrow. In parallel, a split tolerance evolves: the frequency of class I MHC-reactive Lyt-2+ cytotoxic T lymphocyte precursor (CTIrp)- and interleukin 2 (IIr2)- producing T cells falls off in the peripheral lymphoid tissue, but remains unaltered intrathymically. In particular, high affinity CTLp become clonally undetectable. In vivo generation of tolerant cells is cyclosporin A resistant, but dependent on recipient L3T4+ T cells. Loss of Lyt-2+ CTIrpand IL-2-producing T cell precursors is not due to active suppression, but is caused by clonal anergy. Donor-derived chimeric cells positively selected 7 d after intravenous transfusion exhibit in vitro the hallmarks of veto cells, i.e., paralyze CTLp reactive to donor-type class I MHC alloantigens. We conclude that the peripheral (split) tolerance induced in vivo by pretransplant transfusion operates because donor-type cells develop in vivo efficiently into "veto cells;" which in turn induce a state of clonal anergy within antigen-reactive Lyt-2+ T lymphocytes. © 1990, Rockefeller University Press., All rights reserved.