Distinct Inflammatory Signals Have Physiologically Divergent Effects on Epigenetic Regulation of Foxp3 Expression and Treg Function

Lal, Girdhari; Yin, Na; Xu, Jiangnan; Lin, Marvin; Schroppel, S.; Ding, Yaozhong; Marié, Isabelle; Levy, David E.; Bromberg, Jonathan S.

doi:10.1111/j.1600-6143.2010.03389.x

Cited by 56 publications

(49 citation statements)

References 42 publications

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“…Very little information exists about a role for IRF1 in Treg-cell suppression. The Foxp3 promoter contains IRF1-responsive elements, negatively regulating its transcription [46]. However, we could not detect any Foxp3 downregulation in tumor-infiltrating compared with peripheral Treg cells, or in IL-10-producing versus IL-10-negative Treg cells.…”

Section: Discussioncontrasting

confidence: 76%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

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Section: Discussioncontrasting

confidence: 76%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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“…We believe that this finding indicates a role for PGN treatment in the suppression of Treg cell differentiation. This is in line with previous studies by Lal et al and Prinz et al [35,36]. However, the relationship between reduced Treg cells and enhanced Th17 cell responses is not clear, given that Treg cells are not so effective in the control of Th17 responses as in the suppression of Th1 responses [37,38].…”

Section: Discussionsupporting

confidence: 88%

Engagement of Toll-like receptor 2 enhances interleukin (IL)-17+ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells

Wei

Dong

Xiao

et al. 2014

Clinical and Experimental Immunology

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SummaryFunctional analysis of single Toll-like receptors (TLRs) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR-2 agonists on the autoreactive T helper type 17 (Th17) response in experimental autoimmune uveitis (EAU). Treatment by peptidoglycan (PGN), a specific TLR-2 agonist, remarkably increased mRNA levels of Th17-lineage genes interleukin (

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“…27,30,31 Transplanted Tregs localized in scaffold islet grafts remained protective despite the plasticity of these cells in inflammatory environments and were able to protect islets from destruction by infiltrating CD4 and CD8 T cells. 32,33 Treg production of immunomodulatory factors and direct cell-cell interactions may underlie the mechanism of protection, with previous reports indicating Treg control of DC and T-cell maturation and migration to dLN. 6,7 Systemically, a second islet graft without Tregs implanted in a distal location & 100 days after the initial islet transplant with Tregs was protected from autoimmune destruction in transplant recipients in which permanent protection was observed.…”

Section: Discussionmentioning

confidence: 99%

PLG Scaffold Delivered Antigen-Specific Regulatory T Cells Induce Systemic Tolerance in Autoimmune Diabetes

Graham

Zhang

Goodman³

et al. 2013

Tissue Engineering Part A

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Islet transplantation is a promising treatment for human type 1 diabetes mellitus. Transplantation requires systemic immunosuppression, which has numerous deleterious side effects. Islet antigen-specific regulatory T cells (Tregs) have been shown to protect islet grafts from autoimmune destruction in the nonobese diabetic (NOD) model when co-localized in the kidney capsule. An extra-hepatic transplant site was established by transplanting islet-loaded microporous poly (lactide-co-glycolide) (PLG) scaffolds into abdominal fat. This study examined an autoimmune transplantation model and determined whether co-localized Tregs could protect islet grafts in an extra-hepatic and extra-renal transplant site. Normoglycemia was restored, and co-transplanted Tregs extended graft survival, including several instances of indefinite protection. Transplanted Tregs were replaced by recipient-derived Tregs over time, indicating that islet antigen-specific Tregs induce tolerance to islet grafts through host-derived Tregs. Thus, Tregs provided protection against a diverse repertoire of autoreactive T-cell-receptor specificities mediating diabetes in the NOD model, possibly through a phenomenon previously described as infectious tolerance. Interestingly, the infiltration by Tregs protected a second islet transplant, indicating systemic tolerance to islet antigens. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that allows for the co-localization of immunomodulatory cells within islet grafts and induces long-term graft survival in an autoimmune diabetes model. This method of co-localizing immunomodulatory cells with islets in a clinically translatable transplant site to affect the immune system on a local and systemic level has potential therapeutic implications for human islet transplantation.

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Distinct Inflammatory Signals Have Physiologically Divergent Effects on Epigenetic Regulation of Foxp3 Expression and Treg Function

Abstract: Foxp3 expression in regulatory T cells (Treg

Cited by 56 publications

References 42 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Engagement of Toll-like receptor 2 enhances interleukin (IL)-17+ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells

PLG Scaffold Delivered Antigen-Specific Regulatory T Cells Induce Systemic Tolerance in Autoimmune Diabetes

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