A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

D’Alise, Anna Morena; Ergün, Ayla; Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe

doi:10.1073/pnas.1105364108

Cited by 34 publications

(34 citation statements)

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“…It is therefore likely that diminished TGF-b from Tregs may not be an important contributing factor to dysregulation. A recent report demonstrates that although TGF-induced Tregs fro diabetes prone NOD mice expressed FoxP3, they were defective in suppressive activity [37], confirming our hypothesis that there is a TGF-mediated defect in Treg in NOD mice.…”

Section: Discussionsupporting

confidence: 83%

Downregulation of TGF-βRII in T effector cells leads to increased resistance to TGF-β-mediated suppression of autoimmune responses in type I diabetes

et al. 2012

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Tregs play an important role in controlling immune responses, particularly autoimmunity. In NOD mouse model, an excellent model for autoimmune diabetes, transfer of Tregs was shown to prevent diabetes, whereas depletion of Tregs in vivo enhanced disease progression, suggesting that Treg dysfunction contributes to the pathogenesis of diabetes. However, the mechanisms leading to Treg dysfunction and their role in diabetes progression has remained unclear. In this study we assessed quantitative and qualitative changes in Tregs during the development of autoimmune diabetes in NOD. We compared female NOD with males that have similar predisposition to but a lower incidence of diabetes and found that Treg numbers remained unchanged between 6 to 16 weeks of age in both groups. Although female Tregs produced lower TGF-β compared to male, regulatory function of female Tregs was only marginally inferior to male upon GAD65 autoantigen stimulation. GAD65-reactive female Teffectors were more responsive and progressively became refractory to regulation compared to male effectors, in part due to lower expression of TGF-β RII, accounting for reduced sensitivity to Tregs. Moreover, we unexpectedly found that TGF-β suppressed IFN-γ production to GAD65 antigen in male, not in female responders. These data suggest that TGF-β plays a major role in Teff resistance to regulation and Treg dysfunction, and may account for autoimmune diabetes. Our study implies that development of a successful supplemental Treg therapy for halting autoimmunity may require further understanding of Teff responses to regulation in order to generate highly effective Tregs.

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Section: Discussionsupporting

confidence: 83%

Downregulation of TGF-βRII in T effector cells leads to increased resistance to TGF-β-mediated suppression of autoimmune responses in type I diabetes

et al. 2012

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“…As exemplified on the level of Foxp3 upregulation, sGARP protein from 3 independent sources with and without different Fc domains featured comparable activity (supplemental Figure 2C). In accordance with its function as a receptor for latent TGFb, [13][14][15]23,24,27 we next assessed the role of TGF-b in the regulatory activity of sGARP. TGF-b production in naïve CD4 1 T cells in the presence of sGARP was analyzed on protein and mRNA levels (Figure 2A).…”

Section: Results Sgarp Enhances Foxp3 Expression and Represses Prolifmentioning

confidence: 99%

“…[13][14][15]23,24 To address its Treg-independent immune regulatory potential, we generated a recombinant sGARP consisting of the GARP ectodomain (aa 20-627) fused to the Fc-domain of rabbit IgG (supplemental Figure 1). Activation of cord blood-derived naïve CD4…”

Section: Results Sgarp Enhances Foxp3 Expression and Represses Prolifmentioning

confidence: 99%

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

Hahn

Stahl

Becker

et al. 2013

Blood

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Key Points• GARP efficiently represses proliferation of naïve and resting CD4 1 T cells and is involved in the induction of adaptive regulatory T cells.• In vivo, GARP prevents T cell-mediated destructive inflammation in a preclinical humanized mouse model of GVHD.Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-b (TGF-b). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4 1 T cells.We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve

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“…In contrast to the similarly efficient induction of Foxp3 expression by TGF-β, it has recently been shown that thus generated NOD (but not B6) Treg cells are functionally defective [18]. The molecular basis of this impaired function correlated with a decreased expression of a cluster of genes in NOD (as compared to B6) Treg cells, including CD122 [18]. We therefore Figure 1A.…”

Section: Similar Tgf-β-mediated Induction Of Foxp3-expression In Nod mentioning

confidence: 99%

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

et al. 2013

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Regulatory T (Treg) lymphocytes play a central role in the control of autoimmune pathology. Any alteration in Treg-cell biology in mouse strains used for the study of these disorders therefore raises the question of its direct link with disease susceptibility. Paradoxically, in non-obese diabetic (NOD) mice increased numbers of Treg cells develop in the thymus. In this report we identify a locus of <7 Mbp that quantitatively controls Treg-cell development in the thymus of the NOD mouse. This 'Trd1' region is located centromeric to the H2 complex on chromosome 17 and does not include genes encoding classical MHC molecules. The genomic region identified here contains the Idd16 diabetes susceptibility locus and the use of congenic mouse strains allowed us to investigate the potential link between quantitatively altered thymic Treg cells and diabetes susceptibility. Hybrid mice present similar levels of thymic Treg cells as B6 animals but they developed diabetes with the same kinetics as NOD mice. Therefore, the increased Treg-cell development in NOD mice controlled by Trd1 is functionally dissociated from the susceptibility of NOD to diabetes. Keywords: Differentiation r Regulatory T (Treg) cells r Thymus r T1DAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionType I diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing pancreatic β cells. How, when, and why peripheral immunological tolerance is progressively lost and the disease is initiated, is a matter of investigation. One of Correspondence: Dr. Paola Romagnoli e-mail: Paola.Romagnoli@inserm.fr the major players in the maintenance of peripheral tolerance are natural occurring CD4 + (CD25 + )Foxp3 + regulatory T (Treg) cells [1]. Treg cells can prevent diabetes and even reverse established pathology in non-obese diabetic (NOD) mice [2][3][4]. Interestingly, an age-dependent decline in the in vitro and in vivo function of NOD CD4 + CD25 + Treg cells was reported [5,6]. This conclusion * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1356-1362 Molecular immunology 1357 was challenged and it was suggested that the decline may reflect contamination of the CD4 + CD25 + "Treg" cells with Foxp3 − cells that lack regulatory capacity [7]. However, control of diabetogenic T-cell activity may still be defective since conventional T (Tconv) cells from older NOD mice were found to be relatively resistant to suppression by Treg cells [5,6,8]. Importantly, a recent study showed that the TCR-repertoire of Treg cells may be less diverse in NOD than in B6 mice [9]. It remains therefore unclear if the NOD Treg-cell population would have a functional in vivo defect. Natural Treg cells are generated in the thymus where the processes of positive and negative selection shape their autospecific TCR repertoire [10]. Two groups have shown quantitative differences in Treg-cell development in NOD mice [11,12]. Feuerer et al. [11] reported incr...

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A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

Cited by 34 publications

References 50 publications

Downregulation of TGF-βRII in T effector cells leads to increased resistance to TGF-β-mediated suppression of autoimmune responses in type I diabetes

Downregulation of TGF-βRII in T effector cells leads to increased resistance to TGF-β-mediated suppression of autoimmune responses in type I diabetes

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

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