Peng, Y. et al. TGF- regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc. Natl. Acad. Sci. USA 101, 4572−4577

Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2004; 101(13):4572-7. DOI: 10.1073/pnas.0400810101
Source: PubMed


CD4+CD25+ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor beta (TGF-beta) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4+CD25+ T cell pool. Approximately 40-50% of intraislet CD4+ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-beta expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-beta inhibits autoimmune diseases via regulation of the size of the CD4+CD25+ regulatory T cell pool in vivo.

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    • "In our previous study [29] and that performed by Akinci et al. [30] decreased TGFβ1 levels were found in Hashimoto's thyroiditis. On the other hand, over-expression of TGFβ1 in pancreatic islets expands the T reg population and protects non-obese diabetic mice against type I diabetes — another T cell-mediated disease [31]. The two polymorphisms at codon 10 and 25 are within the 29- amino acid signal sequence. "
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    ABSTRACT: The etiopathogenesis of Hashimoto's thyroiditis (HT) - has not been clearly elucidated although the role of chronic inflammation, endothelial dysfunction, and imbalance between pro- and anti-inflammatory cytokines has been established. Transforming growth factor β1 (TGFβ1) is required to maintain immune homeostasis, and is implicated in lymphocyte infiltration, production of autoantibodies and thyrocyte destruction seen in patients with HT. The aim of the present study was to investigate the possible association of Leu10Pro (c.869T>C) and Arg25Pro (c.915G>C) single nucleotide polymorphisms (SNPs) of TGFβ1 gene with the occurrence of HT. We analyzed the genotype and allele frequencies of polymorphisms at codon 10 and 25 in 178 patients who had been diagnosed as having HT and 197 healthy controls using PCR-restriction fragment length polymorphism (RFLP). There was no notable risk for HT afflicted by Leu10Pro (c.869T>C) polymorphism of TGFβ1 gene. However, there was a significant increase of Arg25Pro (c.915G>C) C allele frequency in patients with HT compared with healthy controls (p=0.003, OR=1.87, 95% CI=1.23-2.84). Moreover, heterozygous (CG) subjects had a 2.53-fold increased risk for developing HT with respect to wild (GG) homozygotes (p<0.001, 95% CI=1.57-4.05). TSH levels in CG heterozygous patients were increased in comparison with wild homozygotes (p=0.006). This study indicates that the Arg25Pro (c.915G>C) polymorphism of TGFβ1 gene may be related to increased risk for HT. Copyright © 2015. Published by Elsevier B.V.
    International immunopharmacology 07/2015; 28(1):521-524. DOI:10.1016/j.intimp.2015.07.019 · 2.47 Impact Factor
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    • "TGF-β was originally recognized for its pro-inflammatory properties, but identification of its powerful suppressive activities focused attention for the last decades on dissecting its mechanisms on immune inhibition [2]–[5]. Just as quickly as TGF-β-mediated regulation of regulatory T cells became evident [6], [7], a surprising finding that TGF-β induced differentiation of pro-inflammatory Th17 cells emphasized a broader ability in dictating inflammatory events [8]–[12]. Whereas the role of TGF-β as a T cell-intrinsic signal has been well established in Th17 differentiation, much remains to be discovered in DC-dependent Th17 differentiation in the complex milieu of inflammation. "
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    ABSTRACT: While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets.
    PLoS ONE 07/2014; 9(7):e102390. DOI:10.1371/journal.pone.0102390 · 3.23 Impact Factor
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    • "Treatment with neutralizing antibodies to TGF-β to susceptible mice results in resistance to Leishmania infection (22). Besides, TGF-β is also important for the in vivo expansion of CD4+CD25+ Treg cells (23). Tregs isolated from TGF-β-deficient mice are defective in their suppressive property (24). "
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    ABSTRACT: Visceral leishmaniasis (VL), caused by Leishmania donovani, is a systemic infection of reticulo-endothelial system. There is currently no protective vaccine against VL and chemotherapy is increasingly limited due to appearance of drug resistance to first line drugs such as antimonials and amphotericin B. In the present study, by using a murine model of leishmaniasis we evaluated the function played by soluble leishmanial antigen (SLA)-pulsed CpG-ODN-stimulated dendritic cells (SLA-CpG-DCs) in restricting the intracellular parasitic growth. We establish that a single dose of SLA-CpG-DC vaccination is sufficient in rendering complete protection against L. donovani infection. In probing the possible mechanism, we observe that SLA-CpG-DCs vaccination results in the significant decrease in Foxp3(+)GITR(+)CTLA4(+)CD4(+)CD25(+) regulatory T cells (Treg) cell population in Leishmania-infected mice. Vaccination with these antigen-stimulated dendritic cells results in the decrease in the secretion of TGF-β by these Treg cells by possible regulation of the SMAD signaling. Moreover, we demonstrate that a CXC chemokine, IFN-γ-inducible protein 10 (IP-10; CXCL10), has a direct role in the regulation of CD4(+)CD25(+) Treg cells in SLA-CpG-DC-vaccinated parasitized mice as Treg cells isolated from IP-10-depleted vaccinated mice showed significantly increased TGF-β production and suppressive activity.
    Frontiers in Immunology 06/2014; 5:261. DOI:10.3389/fimmu.2014.00261
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