Tolerance of CD8+ T cells developing in parent-->F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments.
Tolerance of CD8+ cells was examined in parent-->F1 bone marrow chimeras (BMC) prepared with supralethal irradiation; host class I expression in the chimeras was limited to non-BM-derived cells. In terms of helper-independent proliferative responses in vitro and induction of graft-vs.-host disease on adoptive transfer, CD8+ cells from long-term chimeras showed profound tolerance to host antigens irrespective of whether the cells were prepared from the thymus or from spleen or lymph nodes. By limiting dilution analysis, cytotoxic T lymphocyte (CTL) precursors specific for host antigens were rare in the extrathymic lymphoid tissues. In the thymus, by contrast, host-specific CTL precursors were only slightly less frequent than in normal parental strain mice. These host-specific CD8+ cells survived when BMC thymocytes were transferred intravenously to a neutral environment, i.e., to donor strain mice. When transferred to further BMC hosts, however, most of the host-reactive cells disappeared. Collectively, the data suggest that tolerance of CD8+ cells in BMC hosts occurs in both the intrathymic and extrathymic environments. In the thymus, contact with host antigens on thymic epithelial cells deletes CD8+ cells controlling helper-independent proliferative responses and in vivo effector functions but spares typical helper-dependent CTL precursors. After export from the thymus, most of the CTL precursors are eliminated after contacting host antigens on stromal cells in the extrathymic environment.
Kosaka
H
H
Department of Immunology, Scripps Research Institute, La Jolla, California 92037.
Sprent
J
J
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D005720:Gamma Rays; D006086:Graft vs Host Disease / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007116:Immunization, Passive; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D011828:Radiation Chimera; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*
D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I