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      Donor-type CD4 +CD25 + Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

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          Abstract

          Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4 +CD25 + regulatory T (T reg) cells have recently been shown to suppress proliferative responses of CD4 +CD25 T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4 +CD25 + T cells isolated from the spleen or BM of donor C57BL/6 (H-2 b) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4 +CD25 T cells in irradiated BALB/c (H-2 d) hosts in vivo. The addition of the CD4 +CD25 + T reg cells at a 1:1 ratio with responder/inducer CD4 +CD25 T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4 +CD25 + T cells to secrete interleukin 10 and occurred if the T reg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4 +CD25 + T reg and conventional CD4 +CD25 T cells can determine the outcome of aGVHD.

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          Most cited references41

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          An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation

          A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.
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            Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.

            Elimination of CD25+ T cells, which constitute 5-10% of peripheral CD4+ T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen concentration required for stimulating CD25+CD4+ T cells to exert suppression is much lower than that required for stimulating CD25-CD4+ T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25-CD4+ T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25+CD4+ T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25+CD4+ naturally anergic/suppressive T cell population and its functional abnormality directly leads to the development of autoimmune disease.
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              Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β

              CD4+CD25+ T cells have been identified as a population of immunoregulatory T cells, which mediate suppression of CD4+CD25− T cells by cell–cell contact and not secretion of suppressor cytokines. In this study, we demonstrated that CD4+CD25+ T cells do produce high levels of transforming growth factor (TGF)-β1 and interleukin (IL)-10 compared with CD4+CD25− T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-β1 (but not other cytokines), is further enhanced by costimulation via cytotoxic T lymphocyte–associated antigen (CTLA)-4. As in prior studies, we found that CD4+CD25+ T cells suppress proliferation of CD4+CD25− T cells; however, we observed here that such suppression is abolished by the presence of anti–TGF-β. In addition, we found that CD4+CD25+ T cells suppress B cell immunoglobulin production and that anti–TGF-β again abolishes such suppression. Finally, we found that stimulated CD4+CD25+ T cells but not CD4+CD25− T cells express high and persistent levels of TGF-β1 on the cell surface. This, plus the fact that we could find no evidence that a soluble factor mediates suppression, strongly suggests that CD4+CD25+ T cells exert immunosuppression by a cell–cell interaction involving cell surface TGF-β1.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                5 August 2002
                : 196
                : 3
                : 389-399
                Affiliations
                [1 ]Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
                [2 ]Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
                Author notes

                Address correspondence to Samuel Strober, Division of Immunology and Rheumatology, Department of Medicine, CCSR Building, 2215-C, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305. Phone: 650-725-6500; Fax: 650-725-6104; E-mail: sstrober@ 123456stanford.edu

                Article
                20020399
                10.1084/jem.20020399
                2193938
                12163567
                7dbbc96e-5190-4920-afa8-9022df0156eb
                Copyright © 2002, The Rockefeller University Press
                History
                : 12 March 2002
                : 6 June 2002
                : 10 June 2002
                Categories
                Article

                Medicine
                il-10,immune regulation,alloimmunity,t lymphocytes,mixed leukocyte reaction
                Medicine
                il-10, immune regulation, alloimmunity, t lymphocytes, mixed leukocyte reaction

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