Donor-specific tolerance in a murine model: the result of extra-thymic T cell deletion? (original) (raw)
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European Journal of Immunology, 1989
The thymus has been shown to play an important role in the generation of T cell tolerance to self antigens. Developing T cells are readily tolerized to antigens which are expressed in the thymus, and it is generally thought that such thymic tolerance occurs by a mechanism of clonal deletion. We sought to examine whether T cells which initially encountered a "self antigen" post-thymically would be rendered tolerant of that antigen, and if so whether the mechanism of tolerance induction would differ from that found for thymic antigens. We constructed bone marrow radiation chimeras which were grafted with two thymus lobes differing in minor histocompatibility antigens. T cells which matured in one thymus would be tolerized to the minor histocompatibility antigens expressed in that thymus but would not encounter, and' would therefore have no early opportunity of being tolerized to the minor histocompatibility antigens expressed by the other thymus. The initial encounter with the minor antigens on the second thymus would occur post-thymically. Would these T cells be tolerant or responsive to those minor histocompatibility antigens? We found that tolerance was dominant in these chimeras. The data further suggest that the mechanism responsible for tolerance induction in the periphery may differ from that which operates in the thymus.
Journal of Experimental Medicine, 1992
To study the role of thymic education on the development of the human T cell repertoire, SCIDhu mice were constructed with fetal liver and fetal thymus obtained from the same or two different donors. These animals were studied between 7 and 12 mo after transplantation, at which times all thymocytes and peripheral T cells were derived from stem cells of the fetal liver graft. Immunohistology of the thymus grafts demonstrated that thymic epithelial cells were of fetal thymus donor (FTD) origin. Dendritic cells and macrophages of fetal liver donor (FLD) origin were abundantly present in the medullary and cortico-medullary areas. Thymocytes of SCID-hu mice transplanted with liver and thymus of two different donors (FLDA/FTDB animals) were nonresponsive to Epstein-Barr virus-transformed B cell lines (B-LCL) established from both the FLDA and FTDB, but proliferated vigorously when stimulated with third-party allogeneic B-LCL. Mixing experiments showed that the nonresponsiveness to FTDB was not due to suppression. Limiting dilution analysis revealed that T cells reacting with the human histocompatibility leukocyte antigens (HLA) of the FLD were undetectable in the CD8 + T cell population and barely measurable in the CD4 + subset. On the other hand, CD4 + and CD8 + T cells reactive to the HLA antigens of the FTD were readily detectable. These results indicate that FLD-reactive cells were clonally deleted, whereas FTD-reactive cells were not. However, the frequencies of FTD-reactive T cells were consistently twofold lower than those of T cells specific for any third-party B-LCL. In addition, the cytotoxic activity and interleukin 2 production by FTD-specific T cells were lower compared with that of third-party-reactive T cell clones, suggesting that FTD-specific cells are anergic. These data demonstrate that T cells become tolerant to autologous and allogeneic HLA antigens expressed in the thymus via two different mechanisms: hematopoietic cells present in the thymus induce tolerance to "self"-antigens by clonal deletion, whereas thymic epithelial cells induce tolerance by clonal anergy and possibly deletion of high affinity clones. J. Exp.
Biology of Blood and Marrow Transplantation, 2001
A nonmyeloablative conditioning regimen, consisting of depleting doses of anti-CD4 and anti-CD8 monoclonal antibodies (MoAbs) given on days -6 and -1 and 3 Gy of whole body irradiation given on day 0, allows the engraftment of fully major histocompatibility complex (MHC)-mismatched allogeneic bone marrow and the induction of tolerance for the graft. If MoAbs are given on day -5 only, permanent chimerism and tolerance are not observed in most animals. The addition of thymic irradiation to the single MoAb treatment permits tolerance induction in these mice, suggesting that residual host thymocytes reject donor marrow in recipients of 1, but not 2, MoAb injections. In this study, both CD4 + and CD8 + thymocytes were found to be responsible for residual alloreactivity in mice receiving only 1 MoAb injection. Co-receptor coating and downmodulation on residual thymocytes occur to a greater extent in recipients of 2 MoAb injections than in recipients of a single MoAb injection. This downmodulation may play a role in the loss of alloreactivity. Our results suggest that a second MoAb injection inactivates mature, functional donor-alloreactive CD4 + and CD8 + host thymocytes.
European Journal of Immunology, 1995
Athymic mice grafted at birth with allogeneic thymic epithelium (TE) display life-long tolerance to tissue grafts of the TE donor strain, in spite of harboring peripheral T cells capable of rejecting those grafts. Tolerance is maintained in these chimeras by TE-specific regulatory CD4 T cells. We presently address the quantification and the mechanisms of this dominant tolerance process. C57BU6 mice containing variable but defined numbers of peripheral, resident T cells received cell transfers of graded numbers of peripheral T cells from B6(BALB E10) chimeras (C57BL/6 nude mice grafted with T E from 10-day-old BALB/c embryos), resulting in a series of animals containing a wide range of donor (tolerant) versus host (non-tolerant) T cell chimerism. Increasing the relative representation of donor T cells results in a progressive delay in the rejection of BALB/c skin grafts, life-long tolerance being achieved at a ratio of tolerant and non-tolerant T cell populations of 1. In recipients displaying full tolerance, graftreactive non-tolerant T cells were not deleted, anergized or committed to noninflammatory functions. Thus, sorted host T cells from tolerant recipients readily rejected BALB/c skin grafts upon transfer to immunodeficient animals. Finally, measurements of "helper" and inflammatory activities, as well as interleukin-4 and interferon-y production, failed to discriminate between T cell populations from tolerant and non-tolerant animals after specific in vitro stimulation. We conclude that: (a) TE-selected regulatory T cells can suppress, in a quantitative manner, in vivo T cell responses against major and minor histocompatibility antigens expressed by the T E and, (b) this suppressive activity neither inactivates mature non-tolerant T cells, nor does it seem to drive their differentiation along noninflammatory pathways. Abbreviations: E10: Embryonic day 10 B6(BALB E10): C57BL/6 nude grafted with thymic rudiments taken from El0 BALB/c embryos [IR(n)] B 6 C57BL/6 mice irradiated with n rad and reconstituted with bone marrow cells from Rag-ldeficient mice PMR T cells: Peripheral mature resident T cells RTE: Recent thymic emigrants ST: Survival time TE: Thymic epithelium TE-[IR(n)] chimeras: [IR(n)] B6 transferred with T cells from B6(BALB E10)
Proceedings of the National Academy of Sciences, 1995
Athymic mice grafted at birth with allogeneic thymic epithelium (TE) from day 10 embryos before hematopoietic cell colonization reconstitute normal numbers of T cells and exhibit full life-long tolerance to skin grafts of the TE haplotype. Intravenous transfers of splenic cells, from these animals to adult syngeneic athymic recipients, reconstitute T-cell compartments and the ability to reject third-party skin grafts. The transfer of specific tolerance to skin grafts of the TE donor strain, however, is not observed in all reconstituted recipients, and the fraction of nontolerant recipients increases with decreasing numbers of cells transferred. Furthermore, transfers of high numbers of total or CD4+ T cells from TE chimeras to T-cell receptor-anti-H-Y antigen transgenic immunocompetent syngeneic hosts specifically hinder the rejection of skin grafts of the TE haplotype that normally occurs in such recipients. These observations demonstrate (i) that mice tolerized by allogeneic TE and bearing healthy skin grafts harbor peripheral immunocompetent T cells capable of rejecting this very same graft; and (ii) that TE selects for regulatory T cells that can inhibit effector activities of graftreactive cells.