Forkhead Box Protein 3 (FoxP3) Demethylation is Associated with Tolerance Induction in Peanut-Induced Intestinal Allergy

Publication date: Available online 4 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Meiqin Wang, Ivana V. Yang, Elizabeth J. Davidson, Anthony Joetham, Katsuyuki Takeda, Brian P. O'Connor, Erwin W. Gelfand
BackgroundRegulatory T cells (Tregs) play an essential role in the maintenance of immune homeostasis in allergic diseases.ObjectivesTo define the mechanisms underlying induction of tolerance to peanut protein and prevention of the development of peanut allergy.MethodsHigh or low doses of peanut extract (PE) were administered to pups every day for 2 weeks prior to peanut sensitization and challenge. Following challenge, symptoms, Treg numbers, FoxP3, Th2, Th17 cytokine and TGFβ expression in mesenteric lymph node (MLN) CD4⁺ T cells and in jejunum were monitored. Treg suppressive activity and FoxP3 methylation in MLN CD4⁺ T cells were assayed.ResultsFeeding high but not low doses of peanut prior to sensitization induced tolerance as demonstrated by prevention of diarrhea and peanut-specific IgE responses, increases in the percentage of CD4⁺CD25⁺FoxP3⁺ cells in MLN, and FoxP3 mRNA and protein expression in CD4⁺ cells from MLN or jejunum. Feeding high doses of peanut prior to sensitization decreased percentages of CD3⁺CD4⁺IL13⁺ cells and CD3⁺CD4⁺IL17⁺ cells in MLN and decreased IL13, IL17A, and increased TGFβ mRNA expression in the jejunum; numbers of CD103⁺ DC in MLN were significantly increased. Treg suppression was shown to be antigen specific. FoxP3 methylation was increased in PE sensitized and challenged mice, whereas in tolerized mice, levels were significantly reduced.ConclusionsFeeding high doses of peanut to pups induced tolerance to peanut protein. FoxP3 demethylation was associated with tolerance induction, indicating that Tregs play an important role in the regulation of peanut sensitivity and maintenance of immune homeostasis.

Teaser

FoxP3⁺ T regulatory cells are significantly decreased in the jejunum and mesenteric lymph nodes following sensitization and challenge. With induction of tolerance, these numbers are increased as well as demethylation of FoxP3.


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