Abstract
The skin is a major immunologic organ that may induce protection, sensitization or tolerance. Epicutaneous immunotherapy (EPIT) has been proposed as an attractive strategy to actively treat food allergy and has been shown to induce tolerance in sensitized mice through the induction of Foxp3+ regulatory T cells (Tregs), especially CD62L+ Tregs. Among immune cells in the skin, dendritic cells are key players in antigen-specific immune activation or regulation. The role of different populations of skin DCs in tolerance induction remains to be elucidated. Using OVA-sensitized BALB/c mice, we demonstrated that the application of a patch containing OVA-A647 to the skin resulted in allergen uptake by Langerhans cells (LCs) and CD11b+ dermal cDC2 and subsequent migration into skin draining lymph nodes. These 2 populations induced Foxp3 expression in CD4+ cells in vitro. Only LCs induced LAP+ cells and CD62L+ Tregs. Using Langerin-eGFP-DTR mice, we analyzed the role of LCs in the mechanisms of tolerance induction by EPIT in vivo. Following complete depletion of LCs, a dramatic decrease in the number of OVA+ DCs and OVA+ CD11b+ dermal cDC2 was observed in skin draining lymph nodes 48 h after epicutaneous application. Likewise, 2 weeks of EPIT in non-depleted mice induced Foxp3+ Tregs, especially CD62L+, and LAP+ Tregs in skin draining lymph nodes and spleen, whereas no induction of Tregs was observed in LC-depleted mice. Following 8 weeks of treatment, EPIT-treated mice showed significant protection against anaphylaxis accompanied by a significant increase of Foxp3+ Tregs, especially CD62L+ Tregs, which was not seen in the absence of LCs. In summary, although both LCs and CD11b+ dermal cDC2s could induce regulatory T cells, the absence of LCs during EPIT impaired treatment efficacy, indicating their crucial role in skin-induced tolerance.
Highlights
Food allergy is a growing public health concern and manifestations can be severe even life-threatening
After 6 h of application, OVA+ Langerhans cells (LCs) and OVA+ CD11b+ dendritic cells (DCs) were still present in the skin, but to a lesser extent suggesting that some cells had already migrated from skin
Skin and skin draining lymph nodes (sdLNs) results strongly suggest that allergen uptake following epicutaneous application in sensitized mice is mediated by LCs and CD11b+ DCs
Summary
Food allergy is a growing public health concern and manifestations can be severe even life-threatening. Its prevalence increased dramatically during the last decades up to 10% in 2018 [1]. There is no approved cure other than strict avoidance of identified foods and availability of self-injectable epinephrine. Allergen-specific immunotherapy aiming at reduction of the sensitivity to an allergen is an attractive strategy to actively treat food allergy. Proposed imunological mechanisms include decreased allergen-specific IgE and increased IgG4 levels, reduced responses of effector CD4+ T cells, and induction of regulatory T cells (Tregs). Epicutaneous immunotherapy (EPIT) is a novel therapy that is currently under investigation. Safety and efficacy of Viaskin R Peanut in allergic patients has been studied in a recent phase 3 clinical program after positive results in a phase IIb trial [2]
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