Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4-dependent dermal dendritic cells

Abstract : Background: Exposure to allergens, such as house dust mite (HDM), through the skin often precedes allergic inflammation in the lung. It was proposed that T(H)2 sensitization through the skin occurs when skin barrier function is disrupted by, for example, genetic predisposition, mechanical damage, or the enzymatic activity of allergens. Objective: We sought to study how HDM applied to unmanipulated skin leads to T(H)2 sensitization and to study which antigen-presenting cells mediate this process. Methods: HDM was applied epicutaneously by painting HDM on unmanipulated ear skin or under an occlusive tape. HDM challenge was through the nose. Mouse strains lacking different dendritic cell (DC) populations were used, and 1-DER T cells carrying a transgenic T-cell receptor reactive to Der p 1 allergen were used as a readout for antigen presentation. The T(H)2-inducing capacity of sorted skin-derived DC subsets was determined by means of adoptive transfer to naive mice. Results: Epicutaneous HDM application led to T(H)2 sensitization and eosinophilic airway inflammation upon intranasal HDM challenge. Skin sensitization did not require prior skin damage or enzymatic activity within HDM extract, yet was facilitated by applying the allergen under an occlusive tape. Primary proliferation of 1-DER T cells occurred only in the regional skin-draining lymph nodes. Epicutaneous sensitization was found to be driven by 2 variants of interferon regulatory factor 4-dependent dermal type 2 conventional DC subsets and not by epidermal Langerhans cells. Conclusion: These findings identify skin type 2 conventional DCs as crucial players in T(H)2 sensitization to common inhaled allergens that enter the body through the skin and can provoke features of allergic asthma.