The Role of Regulatory T Cells in Epicutaneous Immunotherapy for Food Allergy

In recent decades, a rapid increase in the prevalence of food allergies has led to extensive research on novel treatment strategies and their mechanisms. Mouse models have provided preliminary insights into the mechanism of epicutaneous immunotherapy (EPIT)-induced immune tolerance. In EPIT, antigen applied on the skin surface can be captured, processed, and presented in the lymph nodes (LNs) by Antigen-presenting cells (APCs). In the LNs, induction of regulatory T cells (Treg cells) requires both direct contact during antigen presentation and indirect mechanisms such as cytokines. Foxp3+CD62L+ Treg cells can exhibit the characteristics of hypomethylation of Foxp3 TSDR and Foxp3-LAP+ Treg cells, which increase the expression of surface tissue-specific homing molecules to exert further sustained systemic immune tolerance. Studies have shown that EPIT is a potential treatment for food allergies and can effectively induce immune tolerance, but its mechanism needs further exploration. Here, we review Treg cells’ role in immune tolerance induced by EPIT and provide a theoretical basis for future research directions, such as the mechanism of EPIT and the development of more effective EPIT treatments.

Treatment of Intestinal Inflammation With Epicutaneous Immunotherapy Requires TGF-β and IL-10 but Not Foxp3+ Tregs

Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET).Methods: RAG1−/− mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10−/−, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation.Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10−/− or CD4-dnTGFBRII mice.Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.