Cytotoxic T lymphocyte antigen‐4‐dependent down‐modulation of costimulatory molecules on dendritic cells in CD4<sup>+</sup> CD25<sup>+</sup> regulatory T‐cell‐mediated suppression

Oderup, Cecilia; Cederbom, Lukas; Makowska, Anna; Cilio, Corrado; Ivars, Fredrik

doi:10.1111/j.1365-2567.2006.02362.x

Cited by 283 publications

(201 citation statements)

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“…-1155 Whether a certain CTLA4 expression threshold is necessary to downmodulate CD80/CD86 expression on DCs requires further investigation. CTLA4 has been shown to be involved in Treg cell-mediated inhibition of DC maturation [6,8]. However, it was not known whether CTLA4 alone is sufficient to induce tolerogeneic DCs.…”

Section: Discussionmentioning

confidence: 99%

“…Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9]. However, the molecular mechanisms by which Treg cells modulate DC function remain obscure.…”

Section: Introductionmentioning

confidence: 99%

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Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

2014

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Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cellscan hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate CD4 + and CD8 + T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-κB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection. Keywords: Dendritic cells r Immune regulation r Regulatory T cells r ToleranceAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) play a central role in the initiation and regulation of immune responses [1]. Although traditionally viewed as immunity inducers, in the absence of inflammatory danger signals, DCs participate in the maintenance of peripheral tolerance [2] and can induce T-cell deletion, anergy and generation and expansion of regulatory T (Treg) cells [3]. These tolerogenic DCs show decreased expression of costimulatory molecules such as CD80Correspondence: Dr. Li Zhang e-mail: lzhang@uhnres.utoronto.ca and CD86 and reduced production of proinflammatory cytokines [4]. Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9]. However, the molecular mechanisms by which Treg cells modulate DC function remain obscure. Elucidation of the mechanisms governing DC maturation may facilitate their use in treating a variety of immune-related conditions including autoimmune diseases and transplantation.CD4 + CD25 + Foxp3 + Treg cells play a pivotal role in maintaining self-tolerance and preventing autoimmunity. At least two major subtypes of CD4 + CD25 + Foxp3 + Treg cells have been identified: Thymus-derived natural T regulatory (nTreg) cells and C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1144 Aleksandra Kowalczyk et al. Eur. J. Immunol. 2014. 44: 1143-1155 ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

2014

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Section: Discussionmentioning

confidence: 99%

“…Collectively, our data suggest that CD4 + CD25 + CD134 + CD39 + Treg cells, in the context of a chronic viral infection such as CMV, may rely on the functions of CTLA-4 and CD39, as the expression of both molecules correlates with suppressive function of CMV-P1-specific T-cell clones. Both of these molecules have been shown to effect suppression of responder cells through interaction with DCs [11,54], indicating a potentially important role for DC interaction in the suppressive function of CD4 + CD25 + CD134 + CD39 + Treg cells.Lastly, we applied our ex vivo methodology in a clinical setting by measuring HIV-Gag-specific responses both before and after commencement of ART in the RESTORE study. We observed that the percentage of CD39 − cells within CD25 + CD134 + HIV-Gag-specific CD4 + T cells at baseline was significantly associated with greater CD4 + T-cell recovery after ART initiation and additionally that this percentage inversely correlated with baseline HIV viral load.…”

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confidence: 99%

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

et al. 2014

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Human Ag-specific CD4 + T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag-specific cells consistently identifies a substantial population of CD4 + CD25 + CD134 + CD39 + T cells that have a Treg-cell-like phenotype and mostly originate from bulk memory CD4 + CD45RO + CD127 low CD25 high CD39 + Treg cells. Viable, Ag-specific CD25 + CD134 + CD39 + T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA-4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV-Gag responses in HIV + patients before and after anti-retroviral therapy (ART). Interestingly, we found that the percentage of CD39 − cells within baseline CD4 + T-cell responses to HIV-Gag was negatively correlated with HIV viral load pre-ART and positively correlated with CD4 + T-cell recovery over 96 weeks of ART. Collectively, our data show that Ag-specific CD4 + CD25 + CD134 + CD39 + T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg-cell-like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics.Keywords: Antigen-specific T cells r CD25 r CD39 r CD134 r FOXP3 r OX40 r Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Laura Cook e-mail: lcook@kirby.unsw.edu.au * These authors contributed equally to this work. The current gold standard marker for the study of Treg cells is Forkhead Box Protein 3 (FOXP3), a constitutively expressed nuclear transcription factor, critical for Treg-cell survival and suppressive function [3]. The key limitation of this marker is that viable cells cannot be isolated, as staining for this intracellular protein involves cell permeabilisation. Also, in the context of activation, this marker loses specificity due to transient, activationinduced up-regulation of FOXP3 in human non-Treg cells [4,5]. An alternative, widely used definition of Treg cells is the combined cell surface expression of high levels of CD25 (IL-2Rα) and low levels of CD127 (IL-7Rα) [6]. Whilst >85% of CD127 low CD25 high Treg cells express FOXP3 and are suppressive ex vivo [6], activated Treg cells cannot be isolated with these markers due to CD127 down-regulation, and CD25 up-regulation, on other subsets of CD4 + T cells following activation by cognate .In 2007, it was shown that murine Treg cells co-express the ectoenzymes CD39 and CD73 [10]. These ectonucleotidases work in concert to convert adenosine triphosphate (ATP), adenosine diphosphate and adenosine monophosphate to immunosuppressive adenosine, which appears to play a role in the suppressive repertoire of Treg cells [10]. Apart from contributing to adenosine produ...

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“…Among these, CD4 + CD25 + Foxp3 + T cells express the immunoglobulin cytotoxic T‐lymphocyte antigen 4 (CTLA‐4), the interleukin (IL)‐2 receptor CD25, and produce inhibitory cytokines such as IL‐10 and transforming growth factor (TGF)‐β 2, 3. CD4 + CD25 + Foxp3 + T cells express CD25 at high levels and sequester IL‐2 accordingly, rendering these T cells prone to apoptosis 4.…”

Section: Introductionmentioning

confidence: 99%

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

Ohira

Nakahara

Konnai

et al. 2016

Immunity, Inflammation and Disease

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CD4+CD25highFoxp3+ T cells suppress excess immune responses that lead to autoimmune and/or inflammatory diseases, and maintain host immune homeostasis. However, CD4+CD25highFoxp3+ T cells reportedly contribute to disease progression by over suppressing immune responses in some chronic infections. In this study, kinetic and functional analyses of CD4+CD25highFoxp3+ T cells were performed in cattle with bovine leukemia virus (BLV) infections, which have reported immunosuppressive characteristics. In initial experiments, production of the Th1 cytokines IFN‐γ and TNF‐α was reduced in BLV‐infected cattle compared with uninfected cattle, and numbers of IFN‐γ or TNF‐α producing CD4+ T cells decreased with disease progression. In contrast, IFN‐γ production by NK cells was inversely correlated with BLV proviral loads in infected cattle. Additionally, during persistent lymphocytosis disease stages, NK cytotoxicity was depressed as indicated by low expression of the cytolytic protein perforin. Concomitantly, total CD4+CD25highFoxp3+ T cell numbers and percentages of TGF‐β+ cells were increased, suggesting that TGF‐β plays a role in the functional declines of CD4+ T cells and NK cells. In further experiments, recombinant bovine TGF‐β suppressed IFN‐γ and TNF‐α production by CD4+ T cells and NK cytotoxicity in cultured cells. These data suggest that TGF‐β from CD4+CD25highFoxp3+ T cells is immunosuppressive and contributes to disease progression and the development of opportunistic infections during BLV infection.

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Cytotoxic T lymphocyte antigen‐4‐dependent down‐modulation of costimulatory molecules on dendritic cells in CD4⁺ CD25⁺ regulatory T‐cell‐mediated suppression

Cited by 283 publications

References 54 publications

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

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Cytotoxic T lymphocyte antigen‐4‐dependent down‐modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T‐cell‐mediated suppression

Cited by 283 publications

References 54 publications

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Human antigen‐specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

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Cytotoxic T lymphocyte antigen‐4‐dependent down‐modulation of costimulatory molecules on dendritic cells in CD4⁺ CD25⁺ regulatory T‐cell‐mediated suppression

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses