The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

Shevach, Ethan M.; Tran, Dat Q.; Davidson, Todd S.; Andersson, John

doi:10.1002/eji.200738111

Cited by 102 publications

(91 citation statements)

References 15 publications

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“…The blockade of TGF-β can also have a direct impact in the de novo induction of FoxP3+ regulatory T cells as has been previously reported (Horwitz et al, 2008;Shevach et al, 2008). The administration of anti-cytokine antibodies lead to slight increases in the clinical score of treated mice compared to control mice that did not receive the antibody, which can be the result of the neutralization of intrinsic protective cytokines.…”

Section: Discussionmentioning

confidence: 57%

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease.We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins.We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3 + cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

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Section: Discussionmentioning

confidence: 57%

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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“…FoxP3 expression could easily be induced in most naive T cells by the addition of exogenous TGF-␤. However, in contrast to mouse CD4 ϩ CD25 Ϫ naive T cells that are converted by TGF-␤ to CD4 ϩ CD25 ϩ Tregs with suppressive activities, the human FoxP3 ϩ T cells induced with TGF-␤ in a single round of stimulation were neither anergic nor suppressive (19,21,49,52,53). Our data show that the VIP-tolerant CD4 ϩ CD25 ϩ FoxP3 ϩ T cells are anergic and suppressive in both mouse and human systems.…”

Section: Peripheral Cd4mentioning

confidence: 54%

“…Zheng et al (34) also demonstrated that TGF-␤ requires CTLA4 early after activation to induce FoxP3 and generate adaptive mouse CD4 ϩ CD25 ϩ Tregs. Considerable controversy exists regarding the regulation of FoxP3 expression in human T cells, and some studies have suggested that TCR stimulation alone is sufficient to induce FoxP3 expression, at least transiently, and that the TGF-␤ produced by activated T cells and the TGF-␤ present in the serum are critically involved in such induction (19,49,52,53). FoxP3 expression could easily be induced in most naive T cells by the addition of exogenous TGF-␤.…”

Section: Peripheral Cd4mentioning

confidence: 99%

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Pozo

Anderson

González‐Rey

2009

The Journal of Immunology

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T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25− T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

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“…In vivo, these conditions were granted through the inflammatory environment and severe lymphopenia of the conditioned recipients. Likewise, in vitro allogeneic activation in the absence of TGF-b-induced similar rates of reversion to Foxp3 À cells, highlighting the critical importance of this cytokine in maintenance of the regulatory phenotype [20]. In recipient mice, high reversion rates combined with strong proliferation of the iTreg led to the accumulation of Thy1.1 1 , presumably alloantigen-specific effector T cells in the recipients' SLO (Fig.…”

Section: Resultsmentioning

confidence: 72%

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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Induced antigen-specific Foxp3 1 T cells (iTreg) are being discussed as a promising alternative to polyclonal natural Foxp3 1 T cells (nTreg) for cell-based therapies, particularly to achieve transplantation tolerance. Using Foxp3eGFP-reporter mice, we here establish an efficient protocol to induce and expand alloantigen-specific iTreg from Foxp3 À CD4 1 T cells with cluster-disrupted DC. These iTreg were mainly CD62L 1 and showed efficient suppressive activity in vitro. However, in contrast to nTreg, adoptively transferred iTreg entirely failed to prevent lethal graft versus host disease (GVHD). Within irradiated recipients, the majority of adoptively transferred Foxp3 1 iTreg, but not Foxp3 1 nTreg quickly reverted to Foxp3 À CD4 1 T cells. We therefore suggest that therapeutic approaches to treat GVHD should rely on nTreg, whereas the use of de novo alloantigen-induced iTreg should be handled with caution since the stability of the regulatory phenotype of the iTreg could be of major concern.Key words: Animal models . Dendritic cells . Graft rejection . Regulatory T cells See accompanying article by commentary by Edinger IntroductionRecent advances have demonstrated that adoptively transferred exogenous Treg can inhibit graft versus host disease (GVHD) [1][2][3]. However, the availability of sufficient numbers of donor Treg for cell-based therapies remains limited [4]. Besides the in vitro expansion of nTreg [5], an obvious approach to solve this problem would be the de novo induction and expansion of Foxp3 1 Treg from abundant naïve CD4 1 T cells with recipient alloantigens [6,7]. Instead of mediating unspecific suppression, such alloantigen-induced Treg potentially could provide the advantage of antigen-specific regulation, thereby reducing the risk of disease relapse and infections [8]. Here, we present an efficient protocol to induce Foxp3 1 Treg by the use of clusterdisrupted allogeneic DC. Such allo DC-induced iTreg were functionally active in vitro and displayed a stable regulatory phenotype upon adoptive transfer into untreated syngeneic recipients. However, when used in experimental acute GVHD, these cells quickly lost Foxp3 expression and, in contrast to nTreg, did not show any protective effect. SHORT COMMUNICATION Results and discussionTo define conditions suited for the de novo induction of alloantigen-specific iTreg, we isolated Foxp3 À CD4 1 T cells from C57BL/6 Foxp3EGFP mice and co-cultured them with BM-derived allogeneic BALB/c DC that were either matured by application of LPS or via ''cluster-disruption'' (CD-DC). Disruption of the Ecadherin-mediated cell-cell contacts induces DC maturation through mechanisms distinct from TLR signaling [9]. Since antigen-loaded CD-DC have been shown to induce tolerance in mice after i.v. injection [9] we established a protocol that allowed the conversion of naïve to Foxp3 expressing cells in vitro in the presence of allogeneic but not syngeneic CD-DC. When compared with LPS-matured DC, CD-DC showed equally high expression of MHC class II, but diminished up...

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The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

Cited by 102 publications

References 15 publications

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

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The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

Cited by 102 publications

References 15 publications

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

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Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD