CD4+CD25+T regulatory cells control anti-islet CD8+T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes

Green, Elizabeth A.; Gorelik, Leonid; McGregor, Catrin M.; Tran, Elise; Flavell, Richard A.

doi:10.1073/pnas.1834400100

Cited by 386 publications

(280 citation statements)

References 31 publications

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“…Some studies have suggested a correlation between Treg function and the expression of a latent, membranebound form of TGF-b1 on CD4 + CD25 + Treg cells [28][29][30]. While these studies promote the view that CD4 + CD25 + Treg cells act as carriers of TGF-b1 to activated effector T cells, the alternate view is that surface TGF-b1 may be bound to TGF-b-signaling receptors and initiate a TGF-b signal in Treg cells themselves.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, Oida et al reported that TGF-bdependent suppression was observed in the LAP + CD4 + CD25 -T cell subset [33]. In addition, some studies have suggested a correlation between Treg effector function and the expression of a latent, membrane-bound form of TGF-b1 on CD4 + CD25 + Treg cells isolated from inflamed lymphoid tissues draining target organs undergoing autoimmune attack [30]. However, these studies did not conclusively show functional evidence for a direct effect of Treg cellderived TGF-b1 on responder T cells.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that Smad3-dependent TGF-b signaling in effector CD4 + T cells is not required for CD4 + CD25 + Treg cell-mediated control of bacterial-driven mucosal inflammation. Some studies have suggested a correlation between Treg function and the expression of a latent, membranebound form of TGF-b1 on CD4 + CD25 + Treg cells [28][29][30]. While these studies promote the view that CD4 + CD25 + Treg cells act as carriers of TGF-b1 to activated effector T cells, the alternate view is that surface TGF-b1 may be bound to TGF-b-signaling To determine whether non-CD4 + CD25 + Treg cellderived TGF-b plays any role in suppressing the pathogenic potential of effector T cells, 1 Â 10 6 CD4 + CD25 -T cells were transferred alone into RAG2 -/-mice with or without the administration of a neutralizing anti-TGF-b antibody or an isotype control, and the recipients were monitored for the incidence and severity of IBD.…”

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TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

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Naturally occurring CD4 + CD25 + regulatory T cells (Treg) are potent suppressors of CD4 + and CD8 + T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4 + CD25 + Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-b1 and effector T cell responsiveness to TGF-b in CD4 + CD25 + T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4 + CD25 + Treg cells from either TGF-b1 +/+ or neonatal TGF-b1 -/-mice can suppress the incidence and severity of IBD as well as colonic IFN-c mRNA expression induced by WT CD4 + CD25 -effector T cells. Furthermore, TGF-b-resistant Smad3 -/-CD4 + CD25 + Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3 -/-CD4 + CD25 -effector T cells. Finally, anti-TGF-b treatment exacerbates the colitogenic potential of CD4 + CD25 -effector T cells in the absence of CD4 + CD25 + Treg cells.Together, these data demonstrate that in certain situations CD4 + CD25 + T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-b1 or effector T cell/Treg cell responsiveness to TGF-b via Smad3. IntroductionCD25 (IL-2Ra chain)-expressing CD4 + T cells, which constitute 5-10% of normal CD4 + T cells, play a critical role in the induction and maintenance of peripheral tolerance [1,2]. These naturally occurring CD4 + CD25 + regulatory T (Treg) cells consist of an anergic lymphocyte population with potent immunosuppressive functions in vivo, as the depletion of CD25-expressing CD4 + T cells correlates with increased immunity to tumors, grafts and intracellular pathogens and provokes the induction of multiple inflammatory diseases including autoimmmune gastritis (AIG) and inflammatory bowel disease (IBD) [3,4]. Currently, the mechanism(s) by which CD4 + CD25 + Treg cells mediate suppression in vitro and in vivo is unclear. Following TCR activation, CD4 + CD25 + Treg cells suppress the in vitro proliferation and cytokine production of CD4 + and CD8 + T cells in an antigen nonspecific, but contact-dependent manner that does not appear to involve modulation of APC function [5][6][7]. The role of regulatory cytokines in CD4 + CD25 + Treg cell control of inflammation in vivo appears to be tissue and/ or context-dependent. While CD4 + CD25 + Treg cells from IL-4 -/-and IL-10 -/-mice are as effective as WT CD4 + CD25 + T cells in mediating suppression of AIG, CD4 + CD25 + Treg cells from IL-10 -/-mice cannot control IBD induced by antigen-experienced effector T cells [8,9]. Similarly, IL-10 -/-CD4 + CD25 + Treg cells, in contrast to WT cells, fail to attenuate effector T cell responses to Leishmania major in resistant C57BL/6 mice [10].TGF-b1 is a potently suppressive cytokine that plays a critical role in the regulation of immune function, a...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

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“…However, other factor(s) that, in addition to IL-10, are necessary to drive the suppressive capacity of the Treg could be involved. One potential candidate would be the membrane-bound form of TGF-b, which is discussed as a possible marker for Treg [27]. Treg expressing TGF-b may suppress effector CD8 + T cells either directly through TGF-b/TGF-b receptor interaction or indirectly by blocking antigen-presenting cells, which would underline the necessity of cell-cell contact in addition to the soluble factor IL-10.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺CD25⁺ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

et al. 2006

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CD4 + CD25 + regulatory T cells (Treg) exert suppressive functions on effector T cells in vitro and in vivo. However, the exact cellular events that mediate this inhibitory action remain largely unclear. To elucidate these events, we used intravital microscopy in a model of contact hypersensitivity (CHS) and visualized the leukocyte-endothelium interaction at the site of antigen challenge in awake C57BL/6 mice. Injection of Treg i.v. into sensitized mice at the time of local hapten challenge significantly inhibited rolling and adhesion of endogenous leukocytes to the endothelium. A similar inhibition of leukocyte recruitment could be recorded after injection of Treg-derived tissue culture supernatant. Thus, these data indicate that soluble factors may account for the suppressive effects. Accordingly we found that IL-10, but not TGF-b, was produced by Treg upon stimulation and that addition of anti-IL-10 antibodies abrogated the suppressive effects of Treg and tissue culture supernatant in CHS reactions. Moreover, CD4 + CD25 + T cells isolated from IL-10 -/-mice were not able to suppress the immune response induced by hapten treatment in C57BL/6 mice. In conclusion, our data suggest that cytokine-dependent rather than cell-cell contact-dependent mechanisms play a pivotal role in the suppression of CHS reactions by Treg in vivo.

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“…Also, Treg isolated from secondary lymphoid organs of normal mice do not produce IL-10 or TGF-b upon re-stimulation. In contrast, there is evidence that IL-10 and TGF-b may be relevant mediators of suppression in vivo [6][7][8][9][10][11] and Treg isolated from sites of active immune reactions are able to produce high amounts of IL-10 upon re-stimulation [7,11,12]. Recent data indicate that IL-2 is critical for the activation of Treg effector function, such as production of IL-10.…”

Section: Introductionmentioning

confidence: 99%

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

2005

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Although CD4 + CD25 + regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.

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CD4⁺CD25⁺T regulatory cells control anti-islet CD8⁺T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes

Cited by 386 publications

References 31 publications

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

CD4⁺CD25⁺ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

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CD4+CD25+T regulatory cells control anti-islet CD8+T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes

Cited by 386 publications

References 31 publications

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

CD4+CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

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CD4⁺CD25⁺T regulatory cells control anti-islet CD8⁺T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

CD4⁺CD25⁺ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango