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      Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

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          Abstract

          Abnormalities in CD4 +CD25 +Foxp3 + regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127 lo T reg cells and CD127 hi conventional T cells within the CD25 +CD45RO +RA effector/memory and CD45RA +RO naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25 +CD127 lo cells comprised 6.35 ± 0.26% of CD4 + T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127 lo phenotype were highly correlated within the CD4 +CD25 + population. Moreover, both effector/memory and naive CD25 +CD127 lo cells manifested suppressive activity in vitro, whereas CD25 +CD127 hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.

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          Most cited references27

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          Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

          Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
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            CD4+CD25high regulatory cells in human peripheral blood.

            Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
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              Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.

              Mice deficient for interleukin-2 develop normally during the first 3-4 weeks of age. However, later on they become severely compromised, and about 50% of the animals die between 4 and 9 weeks after birth. Of the remaining mice, 100% develop an inflammatory bowel disease with striking clinical and histological similarity to ulcerative colitis in humans. The alterations of the immune system are characterized by a high number of activated T and B cells, elevated immunoglobulin secretion, anti-colon antibodies, and aberrant expression of class II major histocompatibility complex molecules. The data provide evidence for a primary role of the immune system in the etiology of ulcerative colitis and strongly suggest that the disease results from an abnormal immune response to a normal antigenic stimulus.
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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
                10 July 2006
                : 203
                : 7
                : 1693-1700
                Affiliations
                [1 ]Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, Newtown, NSW 2042, Australia
                [2 ]Centre for Immunology, St. Vincents Hospital, Darlinghurst, NSW 2010, Australia
                [3 ]National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW 2052, Australia
                [4 ]Department of Paediatrics, University of Sydney, Western Clinical School, Penrith, NSW 2751, Australia
                [5 ]Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612
                [6 ]Department of Gastroenterology, The Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
                [7 ]The Children's Hospital at Westmead, NSW 2145, Australia
                Author notes

                CORRESPONDENCE Barbara Fazekas de St. Groth: b.fazekas@ 123456centenary.usyd.edu.au

                Article
                20060468
                10.1084/jem.20060468
                2118333
                16818676
                a69fce6f-1aeb-4669-a09f-f11bdb522927
                Copyright © 2006, The Rockefeller University Press
                History
                : 28 February 2006
                : 6 June 2006
                Categories
                Brief Definitive Reports
                Brief Definitive Report

                Medicine
                Medicine

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