The efficacy and the mode of action 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 approximately 5 x 10(7) 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 (CTL-p)- and interleukin 2 (IL-2)-producing T cells falls off in the peripheral lymphoid tissue, but remains unaltered intrathymically. In particular, high affinity CTL-p become clonally undetectable. In vivo generation of tolerant cells is cyclosporin A resistant, but dependent on recipient L3T4+ T cells. Loss of Lyt-2+ CTL-p- and 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 CTL-p 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.

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