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GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

ABSTRACT: Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.

SUBMITTER: Mantel PY

PROVIDER: S-EPMC2222968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Natural Foxp3(+) regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17-driven lung inflammation.

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| S-EPMC2924601 | biostudies-literature

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| S-EPMC3409280 | biostudies-literature

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| S-EPMC4944649 | biostudies-literature

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| S-EPMC3158716 | biostudies-literature

GATA3 controls Foxp3? regulatory T cell fate during inflammation in mice.

Project description:Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation.

| S-EPMC3204837 | biostudies-other

Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma.

Project description:Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3(+) T cells by TGF-beta when stimulated in the presence of all-trans retinoic acid and rapamycin. The "converted" Foxp3(+) T cells that were derived from Th2 memory cells down-regulated GATA-3 and IRF4 and produced little IL-4, IL-5, and IL-13. Instead, the converted Foxp3(+) T cells suppressed the proliferation and cytokine production of Th2 memory cells. More importantly, the converted Foxp3(+) T cells efficiently accumulated in the airways and significantly suppressed Th2 memory cell-mediated airway hyperreactivity, eosinophilia, and allergen-specific IgE production. Our findings reveal the plasticity of Th2 memory cells and provide a strategy for adoptive immunotherapy for the treatment of allergic diseases.

| S-EPMC2889331 | biostudies-literature

TGF-beta1 Inhibits TLR-mediated odontoblast responses to oral bacteria.

Project description:TGF-beta1 exerts diverse functions in tooth development and tissue repair, but its role in microbial defenses of the tooth is not well-understood. Odontoblasts extending their cellular processes into the dentin are the first cells to recognize signals from TGF-beta1 and bacteria in carious dentin. This study aimed to determine the role of TGF-beta1 in modulating odontoblast responses to oral bacteria. We show that these responses depend upon the expression levels of microbial recognition receptors TLR2 and TLR4 on the cell surface. Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum activated both TLRs, but TLR4 played a greater role. Lack of cell-surface TLR2 was associated with poor response to Streptococcus mutans, Enterococcus faecalis, and Lactobacillus casei. TGF-beta1 inhibited TLR2 and TLR4 expression and attenuated odontoblast responses. Our findings suggest that the balance between TLR-mediated inflammation and TGF-beta1 anti-inflammatory activity plays an important role in pulpal inflammation.

| S-EPMC3317952 | biostudies-literature

Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function.

Project description:The transcriptional repressor Bcl6 is a critical arbiter of Th cell fate, promoting the follicular Th lineage while repressing other Th cell lineages. Bcl6-deficient (Bcl6(-/-)) mice develop a spontaneous and severe Th2-type inflammatory disease, thus warranting assessment of Bcl6 in regulatory T cell (Treg) function. Bcl6(-/-) Tregs were competent at suppressing T cell proliferation in vitro and Th1-type colitogenic T cell responses in vivo. In contrast, Bcl6(-/-) Tregs strongly exacerbated lung inflammation in a model of allergic airway disease and promoted higher Th2 responses, including systemic upregulation of microRNA-21. Further, Bcl6(-/-) Tregs were selectively impaired at controlling Th2 responses, but not Th1 and Th17 responses, in mixed chimeras of Bcl6(-/-) bone marrow with Foxp3(-/-) bone marrow. Bcl6(-/-) Tregs displayed increased levels of the Th2 transcription factor Gata3 and other Th2 and Treg genes. Bcl6 potently repressed Gata3 transcriptional transactivation, providing a mechanism for the increased expression of Th2 genes by Bcl6(-/-) Tregs. Gata3 has a critical role in regulating Foxp3 expression and functional fitness of Tregs; however, the signal that regulates Gata3 and restricts its transactivation of Th2 cytokines in Tregs has remained unexplored. Our results identify Bcl6 as an essential transcription factor regulating Gata3 activity in Tregs. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program that is required for specific suppression of Gata3 and Th2 effector responses by Tregs.

| S-EPMC3490013 | biostudies-literature

Interleukin-12 converts Foxp3+ regulatory T cells to interferon-?-producing Foxp3+ T cells that inhibit colitis.

Project description:Regulatory T (Treg) cells are plastic, but the in vivo mechanisms by which they are converted into foxhead box p3 (Foxp3+) interferon (IFN)-?+ T cells and whether these converted cells retain the ability to inhibit colitis are not clear.Foxp3+ Treg cells were generated by culture of naïve CD4+ T cells from Foxp3GFP CBir1 T-cell receptor (TCR) transgenic (Tg) (CBir1-Tg) mice, which are specific for CBir1 flagellin (an immunodominant microbiota antigen), with transforming growth factor-?. Foxp3GFP+ CBir1-Tg Treg cells were isolated by fluorescence-activated cell sorting and transferred into TCR?x?-/- mice. Colitis was induced by transfer of naïve CBir1-Tg CD4+ T cells into immunodeficient mice.Microbiota antigen-specific Foxp3+ Treg cells were converted, in the intestine, to IFN-?+ T-helper (Th)1 cells, interleukin (IL)-17+ Th17 cells, and Foxp3+ T cells that coexpress IFN-? and/or IL-17. Conversion of Treg cells into IFN-?-producing Th1 cells and Foxp3+IFN-?+ T cells required innate cell production of IL-12 in the intestine; blocking IL-12 with an antibody inhibited their conversion to Th1 and Foxp3+IFN-?+ T cells in the intestines of mice that were recipients of Treg cells. Addition of IL-12, but not IL-23, promoted conversion of Treg cells into Th1 and Foxp3+IFN-?+ T cells, in vitro. Foxp3+IFN-?+ T cells had regulatory activity because they suppressed proliferation of naïve T cells, in vitro, and inhibited induction of colitis by microbiota antigen-specific T cells. IFN-?+ Th1 cells were not converted into Treg cells; Foxp3+IFN-?+ T cells differentiated into IFN-?+ but not Foxp3+ T cells.IL-12 promotes conversion of Treg cells into IFN-?-expressing cells; Foxp3+IFN-?+ T cells retain their regulatory functions and develop during the transition of Foxp3+ Treg cells into IFN-?+ Th1 cells.

| S-EPMC3109200 | biostudies-literature

TGF-beta1 regulates TGF-beta1 and FGF-2 mRNA expression during fibroblast wound healing.

Project description:AIMS:To evaluate the expression of transforming growth factor beta1 (TGF-beta1) and fibroblast growth factor 2 (FGF-2) mRNA in stromal cells in response to injury in the presence of either TGF-beta1 or FGF-2. It has been shown previously that heparan sulfate proteoglycans and FGF-2 are present transiently during wound repair in vivo and that an increase in TGF-beta1 mRNA is detected rapidly after injury. METHODS:Primary corneal fibroblasts were cultured to confluency, serum starved, and linear wound(s) were made in medium containing TGF-beta1 or FGF-2. TGF-beta1 and FGF-2 mRNA expression were evaluated using both northern blot analysis and in situ hybridisation. Both dose dependent and time course experiments were performed. Whole eye organ culture experiments were also carried out and growth factor expression was assessed. RESULTS:Injury and exogenous TGF-beta1 increased TGF-beta1 mRNA values. The increase in expression of FGF-2 mRNA was not detected until wound closure. In contrast, FGF-2 inhibited the expression of TGF-beta1. TGF-beta1 increased TGF-beta1 mRNA stability but did not alter that of FGF-2. Migration assay data demonstrated that unstimulated stromal cells could be activated to migrate to specific growth factors. CONCLUSIONS:TGF-beta1 specifically enhances cellular responsiveness, as shown by increased stability after injury and the acquisition of a migratory phenotype. These data suggest that there is an integral relation during wound repair between TGF-beta1 and FGF-2.

| S-EPMC1187169 | biostudies-literature

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