Epicutaneous allergen immunotherapy induces a profound and selective modulation in skin dendritic-cell subsets

Epicutaneous immunotherapy (EPIT) protocols have recently been developed to restore tolerance in patients with food allergy. The mechanisms by which EPIT protocols promote desensitization rely on a profound immune deviation of pathogenic T- and B-cell responses.To date, little is known about the contribution of skin dendritic cells (skDCs) to T-cell remodeling and EPIT efficacy.We capitalized on a preclinical model of food allergy to ovalbumin (OVA) to characterize the phenotype and functions of OVAsup+/supskDCs throughout the course of EPIT.Our results showed that both Langerhans cells and dermal conventional cDC1 and cDC2 subsets retained their ability to capture OVA in the skin and to migrate toward the skin-draining lymph nodes during EPIT. However, their activation/maturation status was significantly impaired, as evidenced by the gradual and selective reduction of CD86, CD40, and OVA protein expression in respective subsets. Phenotypic changes during EPIT were also characterized by a progressive diversification of single-cell gene signatures within each DC subset. Interestingly, we observed that OVAsup+/supLangerhans cells progressively lost their capacity to prime CD4sup+/supTsubEFF/subcells, but gained regulatory T-cell stimulatory properties. In contrast, cDC1 were inefficient in priming CD4sup+/supTsubEFF/subcells or in reactivating TsubMEM/subcells in vitro, whereas cDC2 retained moderate stimulatory properties, and progressively biased type 2 immunity toward type 1 and type 17 responses.Our results therefore emphasize that the acquisition of distinct phenotypic and functional specializations by skDCs during EPIT is at the cornerstone of the desensitization process.