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

Abstract

The role of T regulatory cells (Tregs) in the control of peanut sensitivity and tolerance induction is not well-defined. High (0.5 mg/gram body weight) or low doses (0.05 mg/gram body weight) of peanut extract (PE) were administered to pups every day for 2 weeks prior to peanut sensitization and challenge. Anti-CD25 was administered prior to peanut sensitization and challenge. Symptoms, intestinal inflammation, and Treg numbers in mesenteric lymph nodes (MLN) were monitored. FoxP3 methylation in genomic DNA from MLN CD4+T cells was detected by bisulfite pyrosequencing. Feeding high but not low doses of peanut prior to sensitization induced tolerance to peanut protein, prevented diarrhea and intestinal inflammation and increased the percentage of CD4+CD25+FoxP3+cells in MLN. Mice treated with anti-CD25 reversed established tolerance with reappearance of all manifestations of sensitivity. FoxP3 methylation within the intronic 1 region was significantly increased in sham-fed and PE sensitized and challenged mice compared to non-sensitized but challenged controls. In parallel to induction of tolerance, levels of FoxP3 methylation in 7 of the 9 CpG sites in the intronic 1 region were significantly reduced, to baseline levels, in mice fed high doses of peanut prior to PE sensitization and challenge. Tregs play an important role in the regulation of peanut sensitivity and maintenance of immune homeostasis. FoxP3 demethylation was associated with tolerance induction to peanut protein.