Oral tolerance in the absence of naturally occurring Tregs

Mucida, Daniel; Kutchukhidze, Nino; Erazo, Agustin; Russo, Marco; Lafaille, Juan J.; Lafaille, Maria A. Curotto de

doi:10.1172/jci24487

Cited by 440 publications

(452 citation statements)

References 69 publications

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“…5B). To confirm the above results, we repeated the CNS2 demethylation study using the oral tolerance model (5,54). FACS-sorted naive OT-II T cells were transferred into congenically marked WT B6 mice followed by the administration of OVA to induce pTregs.…”

Section: Vitamin C Is Essential For Cns2 Demethylation In Ptregsmentioning

confidence: 80%

“…1E) and pTregs (Figs. [5][6], suggesting that the uptake of vitamin C through SVCTs is critical in the Tet-mediated CNS2 demethylations. Exceptionally, thymically derived Tregs were resistant to sulfinpyrazone treatment.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is now appreciated that Tregs can be generated not only in the thymus but also in the periphery, and even in vitro from naive CD4 + T cells. Thus, Treg populations can be divided into two groups (4)-namely, thymus-derived Tregs (tTregs) and those that are derived outside the thymus, known as induced Tregs, which can be further classified into two subgroups: Tregs generated in vivo (referred to as peripheral Tregs [pTregs]) (5)(6)(7)(8) and Tregs generated in vitro by TGF-b (referred to as iTregs hereafter) (9). Although all three Treg populations show suppressive activity (10,11) and sometimes can be interchangeable in vivo (12), each type of Treg shows unique genetic (13) and epigenetic (14) profiles, which suggests that each type develops under different environments.…”

Section: Vitamin C Facilitates Demethylation Of the Foxp3 Enhancer Inmentioning

confidence: 99%

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Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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Section: Vitamin C Is Essential For Cns2 Demethylation In Ptregsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Vitamin C Facilitates Demethylation Of the Foxp3 Enhancer Inmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

View full text Add to dashboard Cite

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“…Regulatory T cells can be divided into subsets on the basis of their development (natural or acquired), cell surface phenotype, secreted proteins and function. Acquired Tregs express FOXP3 [3,4] and, like natural Tregs, are dependent on cell contact (acquired Tregs). They are anergic and secrete very little or no IL-2 [5].…”

Section: Introductionmentioning

confidence: 99%

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

Wang

Davies

2007

International Immunopharmacology

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Treatment with a cocktail of CD4 and CD8-specific monoclonal antibodies (mAb) induces long-term transplantation tolerance and regulatory CD4 + T cells that induce tolerance in non-tolerant T cells. In contrast, treatment with a CD4-specific mAb alone fails to induce long-term tolerance. The current study was designed to test the hypothesis that CD8 blockade plays a role in promoting the development of CD4 + regulatory T cells.Using the DO11.10 CD4 + TCR transgenic mouse model we show that treatment with a CD4/CD8-specific mAb cocktail induces antigen-specific tolerance to OVA, measured by a significant decrease in OVA-specific IgG, on challenge with antigen. Although treatment with OVA and the CD4-specific mAb alone also induces a significant decrease in OVA-specific antibody, the number of DO11.10 cells is significantly greater in mice treated with the CD4/CD8-specific mAb cocktail, and this is associated with a significant increase in proliferation of DO11.10 cells in response to specific antigen. DO11.10 cells sorted from mice made tolerant to OVA with the CD4/CD8-specific mAb cocktail promote an OVA-specific IgG1 (Th2-type) response but not an OVA-specific IgG3 (Th1-type) response on transfer into new syngeneic recipients, suggesting their ability to regulate the type of antigen-specific immune response that ensues after priming with antigen. In addition, DO11.10 cells from tolerant mice express markers that are characteristic of CD4 + regulatory cells, including FOXP3, GITR and CTLA4, but not CD25. Taken as a whole, these data suggest that CD8 blockade promotes CD4 + FOXP3 + regulatory CD4 + T cells by promoting their proliferation in tolerant mice.

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“…Recently, it has been shown that specialized populations of CD4 + /CD25 + regulatory T cells (Treg) control intestinal inflammation induced by immune response, via IL-10-and TGFb1-dependent mechanisms. In addition, naïve peripheral T cells may acquire a Treg phenotype under the influence of TGFb1 [8,33,74].…”

Section: How Tgfb1 Signal Influences Colon Mucosa Functionmentioning

confidence: 99%

TGFβ1 expression in colonic mucosa: modulation by dietary lipids

2007

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Transforming growth factor beta1 (TGFb1) is fundamental to maintain the intestinal epithelial cell homeostasis through its control action on cell proliferation, differentiation and apoptosis. TGFb1 dysregulation has been observed in several chronic human diseases, including ulcerative colitis, Crohn's disease and colon carcinoma. In the first two conditions, a marked oxidative stress is consistently present, while in the third one, levels of reactive oxygen species tend to be significantly lower than in the surrounding normal tissue. Lipid-derived compounds such as the aldehyde 4-hydroxynonenal (HNE) or cholesterol oxidation products (oxysterols) were shown able to induce expression and synthesis of TGFb1, an event which can be detrimental or beneficial, essentially depending on its actual intensity. Understanding how specific dietary lipids may influence the complex molecular signaling underlying this cytokine expression, may provide new indications for therapeutic and preventive strategies in inflammatory bowel diseases and colon carcinoma.

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Oral tolerance in the absence of naturally occurring Tregs

Cited by 440 publications

References 69 publications

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

TGFβ1 expression in colonic mucosa: modulation by dietary lipids

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