Alloantigen-Induced CD25+CD4+ Regulatory T Cells Can Develop In Vivo from CD25-CD4+ Precursors in a Thymus-Independent Process (original) (raw)
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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)
European Journal of Immunology, 1996
Grafts of thymic epithelium (TE) rudiments restore T cell development and function in allogeneic athymic mice. These TE chimeras are specifically tolerant to grafts of peripheral tissues (e.g. skin and heart) from the TE donor strain, although they harbor peripheral immunocompetent T cells capable of rejecting those grafts. Initial analysis has shown that TE chimeras also harbor TE-selected CD4 T lymphocytes that inhibit graft rejection by tissue-reactive T cells in immunocompetent recipients. Peripheral tolerance in TE chimeras is thus maintained by dominant mechanisms dependent on regulatory CD4 T lymphocytes. Here we show that TE-selected regulatory T cells recruit nontolerant tissue-reactive CD4 and CD8 T cells to express similar regulatory functions. Only recent thymic emigrants, but not peripheral resident mature T cells are susceptible to this process of functional education, which also requires exposure to specific antigens and occurs entirely in the periphery. We propose that these mechanisms play a major role in establishing and maintaining natural self tolerance to tissue-specific antigens.
Induction of regulatory T cells from mature T cells by allogeneic thymic epithelial cells in vitro
Transplant International, 2006
Accumulating evidence also showed that thymus plays an important role in self-tolerance, 'infectious tolerance' and other allogeneic tolerance-inducing models [5,10-19]. Neonatal thymectomy increases the incidence of spontaneous and methylcholanthrene-enhanced thyroiditis in rats [20], indicating thymus-produced regulatory cells may play a role in autoantigen tolerance [19,21]. T-cell tolerance to renal allografts in miniature swine is induced across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-day course of cyclosporine A, in contrast to irreversible rejection observed in recipients without cyclosporine A treatment [22]. However, a complete thymectomy of the recipients 21 days before renal transplantation led to the acute cellular rejection of
Immune regulation by regulatory T cells: implications for transplantation
Transplant Immunology, 2003
The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-b. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4 CD25 regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also q q efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.
Basic science for the clinician 32: T-cells with regulatory function
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 2005
Tolerance is one of the major requirements of a successful immune system: destroy invaders but recognize self and the benign environment to leave them alone. Central tolerance is achieved by deletion of T-cells with T-cell antigen receptors that recognize self-antigens too well. However, within the population of T-cells that actually survive the harrowing experience of passage through the thymus (wherein over 98% of all pre-T-cells perish), there persist T-cells capable of inducing autoimmune damage. How then to avoid autoaggression? One theory in the 1970s was that there were peripheral T-suppressor cells that actively dampened these autoimmune proclivities. One problem presented itself, however; despite the fact that such an immunologic activity could be measured, no one could identify the cells that mediated the activity and so the concept fell into disfavor. However, the concept of peripheral regulation by a distinct (at last identifiable!) population of T-cells is now back in v...