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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 references26

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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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            • Abstract: found
            • Article: not found

            T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

            T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
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              • Record: found
              • Abstract: found
              • 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
                44815c10-0a07-4628-b831-b6f708bc6f38
                History
                : 8 June 2011
                : 29 June 2011
                Categories
                Original Articles

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

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