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 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.
Heeg
K
K
Institute of Medical Microbiology and Hygiene, Technical University of Munich, Federal Republic of Germany.
Wagner
H
H
D000818:Animals; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens