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      Homeostatic maintenance of natural Foxp3 + CD25 + CD4 + regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization

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          Abstract

          Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25 + CD4 + T cells, but not CD25 CD4 + T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25 + CD4 + T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25 low CD4 + nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25 + CD4 + regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25 low CD4 + activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

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          Most cited references74

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          Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

          A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
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            Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

            CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
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              Neurotransmitter synthesis and uptake by isolated sympathetic neurones in microcultures.

              Assays of isolated single sympathetic neurones show that their transmitter functions can be either adrenergic or cholinergic depending on growth conditions. The data suggest that the number of transmitters made by most mature individual neurones is restricted.
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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
                7 March 2005
                : 201
                : 5
                : 723-735
                Affiliations
                [1 ]Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
                [2 ]Research Center for Allergy and Immunology, Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan
                [3 ]Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
                Author notes

                CORRESPONDENCE Shimon Sakaguchi: shimon@ 123456frontier.kyoto-u.ac.jp

                Article
                20041982
                10.1084/jem.20041982
                2212841
                15753206
                f1c3679f-2a8c-4e63-806f-48aa5261c239
                Copyright © 2005, The Rockefeller University Press
                History
                : 24 September 2004
                : 18 January 2005
                Categories
                Article

                Medicine
                Medicine

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