TGF  regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo

Schramm, Christoph; Huber, Samuel; Protschka, Martina; Czochra, P.; Burg, Jürgen; Schmitt, Edgar; Lohse, Ansgar W.; Galle, Peter R.; Blessing, Manfred

doi:10.1093/intimm/dxh126

Cited by 101 publications

(84 citation statements)

References 32 publications

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“…Nevertheless, both knockout mice develop lethal lymphoproliferative diseases at an early age, a phenotype that resembles that of Foxp3 À/À mice [22,23]. It has been reported that in peripheral lymphoid organs, both the frequency of Treg cells as well as Foxp3 expression increases with TGF-b1 overexpression and decreases with impairment of TGF-b signaling [24,25]. These studies demonstrated the important role of TGF-b in the constitutive expression of Foxp3.…”

Section: Introductionmentioning

confidence: 72%

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

et al. 2009

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The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3 + Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-b1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-b1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-b1-induced-Treg generation from Smad3 À/À mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-jB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-b1 significantly attenuates NF-jB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-jB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-jB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-b1-induced-Treg cells for therapeutic purposes. There are reports documenting a reduction in the number or function of Treg cells in patients with numerous autoimmune diseases, including diabetes, rheumatoid arthritis, psoriasis, myasthenia gravis or sarcoidosis [12][13][14][15]. Thus, one possible way for restoration of self-tolerance in these patients could be by the infusion of Treg cells having an increased ability to control ongoing autoimmune destruction. Due to the limited availability of nTreg cells, in vitro generated iTreg cells may serve as an alternative source of Treg cells for therapeutic purposes. There is strong evidence that these Foxp3 + iTreg cells can prevent/delay the development of Type 1 Diabetes in the NOD mice [16,17]. Hence, the regulation of Foxp3 expression during iTreg generation is of considerable interest. Relatively little is known about the regulation of Foxp3 in the periphery. The essential roles of IL-2, TGF-b and TCR signaling in iTreg generation have been established [11,[18][19][20]. However, it is unclear which particular arms in each of these pathways are important in FoxP3 regulation. TGF-b1 is a pluripotent cytokine that has pronounced effects on T-cell-mediated immune suppression as well as on the control of autoimmunity. The binding of TGF-b1 to its receptor complex activates the intracellular kinase domain of TGF-bRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non-Smad proteins (Smad-independent pathway) [21]. After forming a heterodimer with phosphorylated Smad4, activated Smad2 and Smad3 translocate to the nucleus where they regulate TGF-b1-dependent gene expression. The generation of nTreg cells from the thymus of TGF...

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Section: Introductionmentioning

confidence: 72%

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

et al. 2009

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“…Consistent with this observation, Green et al have shown that TGFβ signaling-deficient T cells are not inhibited by T reg cells in vivo, suggesting that TGFβ-dependent T reg cells are major factors in tolerance induction [51]. T reg -cell numbers are reduced in the periphery of mice either lacking TGFβR2 or expressing a dn-Tgfbr2 in T cells [14,15,52]. These data suggest that autocrine TGFβ1 in T reg cells is important for their maintenance, expansion and suppressor function.…”

Section: Tgfβ Function In T Reg Cellsmentioning

confidence: 80%

TGFβ1 and Treg cells: alliance for tolerance

Bommireddy

Doetschman

2007

Trends in Molecular Medicine

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Transforming growth factor β1 (TGFβ1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T reg )-cell and effector-cell function and tumorigenesis. Defects in TGFβ1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFβ1 prevents abnormal T-cell activation through the modulation of Ca 2+ -calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T reg cells, its effects are mediated, at least in part, through SMAD signaling. TGFβ1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T h IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFβ1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

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“…The decreased in vivo suppressive capacity of TG CD4 ϩ CD25 ϩ Treg demonstrates that the effect of endogenous TGF-␤ on CD4 ϩ CD25 ϩ Treg themselves is essential for their proper in vivo suppressive capacity. It has previously been demonstrated that the expression of Foxp3, a transcription factor essential for the development and function of CD4 ϩ CD25 ϩ Treg, is modulated by TGF-␤ in vitro (11,12) and in vivo (18). Therefore, Foxp3 might mediate some of the effects induced by TGF-␤.…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells

Huber¹,

Schramm²,

Lehr

et al. 2004

The Journal of Immunology

372

246

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Data regarding the role of TGF-β for the in vivo function of regulatory CD4+CD25+ T cells (Treg) are controversial. A transgenic mouse model with impaired TGF-β signaling specifically in T cells was used to assess the role of endogenous TGF-β for the in vivo function of CD4+CD25+ Treg in a murine model of colitis induced by dextran sulfate. Transfer of wild-type, but not transgenic CD4+CD25+ Treg was found to suppress colitis in wild-type mice. In addition, by transferring CFSE-labeled CD4+CD25+ Treg we could demonstrate that endogenous TGF-β promotes the expansion of CD4+CD25+ Treg in vivo. Transgenic mice themselves developed reduced numbers of peripheral CD4+CD25+ Treg and were more susceptible to the induction of colitis, which could be prevented by the transfer of wild-type Treg. These data indicate that TGF-β signaling in CD4+CD25+ Treg is required for their in vivo expansion and suppressive capacity.

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TGF regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo

Cited by 101 publications

References 32 publications

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

TGFβ1 and Treg cells: alliance for tolerance

Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells

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