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      In vitro induced CD8 + regulatory T cells inhibit skin inflammation

      1 , 2 , 1 , 3 , 3 , 2 , 1 , 1 , 4 , *

      European Journal of Microbiology and Immunology

      Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.

      skin inflammation, immune regulation, CD8+ T cells, immune modulation, TH, T helper cells, Foxp3, forkhead box protein 3, GFP, green fluorescent protein, RA, retinoic acid, DC, dendritic cell, Sp, spleen, CFSE, carboxyfluorescein diacetate, succinimidyl ester, CHS, contact hypersensitivity, DNFB, 2,4-dinitro-1-fluorobenzene, PBMC, peripheral blood mononuclear cells, CD, cluster of differentiation, CTLA, cytotoxic T-lymphocyte antigen, GITR, glucocorticoid-induced tumor necrosis factor receptor, TGF, transforming growth factor, IL, interleukin, TNF-β, tumor necrosis factor-β, IFN-γ, interferon-γ, PASI, Psoriasis Area and Severity Index

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          Abstract

          CD8 + regulatory T cells appear impaired in number and/or function in some autoimmune diseases. However, the role of CD8 + regulatory T cells in the pathogenesis of skin inflammation and psoriasis remains unknown. In this study, we set out to analyze the capability of CD8 + regulatory T cells to inhibit skin inflammation in a murine model and to determine the frequency of CD8 + regulatory T cells in patients with psoriasis. We demonstrate that murine fully competent CD8 + regulatory T cells can be induced by stimulating naïve CD8 + T cells in the presence of TGF-β and retinoic acid (RA). Importantly, in vitro induced CD8 + regulatory T cells significantly suppressed skin inflammation in vivo. Furthermore, we found that the frequency of regulatory CD8 +CD25 +Foxp3 + T cells is decreased in peripheral blood but increased in lesional psoriatic skin of patients with psoriasis. Thus, our study suggests a previously unappreciated role of CD8 +CD25 + Foxp3 + T cells in skin disorders, and induction of these cells in vitro may be an effective immunotherapy for skin inflammation.

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          Most cited references 26

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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            Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.

            The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4(+) T lymphocyte subpopulation in peripheral blood, phenotypically CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4(+) responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high) Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo.
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              • Article: not found

              IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells.

              T memory/effector cells (Tmem/eff) isolated from psoriatic patients are chronically activated and poorly suppressed by regulatory T cells (Treg). The proinflammatory cytokine IL-6, which signals through Stat3, allows escape of Tmem/eff cells from Treg-mediated suppression in a murine system. We show here that IL-6 protein is markedly elevated and most highly expressed by CD31(+) endothelial cells and CD11c(+) dermal dendritic cells (DCs) in lesional psoriatic skin. We hypothesized that exposure to high IL-6 in lesional tissue may lead to the dampened Treg function observed in psoriasis patients. Indeed, we found that IL-6, but not other Stat3-activating cytokines, was necessary and sufficient to reverse human T cell suppression by Treg in an in vitro model using activated DCs as a source of IL-6. IL-6Ralpha and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6Ralpha expression on Treg exceeded that of effector T cells, and both populations phosphorylated Stat3 in response to IL-6. Phosphorylation of Stat3 in T cells contributes to Th17 differentiation and we identify cells within lesional tissue that coexpress CD3, IL-17, and IL-6, indicating that Th17 cells are present in vivo within the psoriatic Tmem/eff population and contribute to IL-6-mediated resistance to Treg suppression. Taken together, T lymphocytes trafficking into lesional psoriatic skin encounter high IL-6 from endothelial cells, DCs, and Th17 cells, enabling cutaneous T cell escape from Treg suppression and Th17 participation in inflammation. Targeting IL-6 signaling pathways in psoriasis may rebalance Treg/T effector activity and ameliorate disease.
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 September 2011
                : 1
                : 3
                : 208-214
                Affiliations
                [ 1 ] Institute of Medical Microbiology, University Hospital, University of Duisburg-Essen, Essen, Germany
                [ 2 ] Department of Dermatology and Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany
                [ 3 ] Department of Dermatology, Venerology and Allergology, University Hospital, University Duisburg-Essen, Essen, Germany
                [ 4 ] Mucosal Immunity Group, Institute of Medical Microbiology, University Hospital Essen, Hufelandstr. 55, D-45122, Essen, Germany
                Author notes
                [* ] +492017231826, +492017235602, astrid.westendorf@ 123456uk-essen.de
                Article
                4
                10.1556/EuJMI.1.2011.3.4
                Categories
                Original Articles

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