Histamine receptor H1 signaling on dendritic cells plays a key role in the IFN-γ/IL-17 balance in T cell-mediated skin inflammation

Background: The diverse effects of histamine on immune regulation are a result of the differential expression and regulation of 4 histamine receptors. Many of the immediate allergic and inflammatory actions of histamine are mediated via the type 1 receptor (H1R). Objectives: We hypothesized that H1R was involved in the fine-tuning of the initiation of T cell-mediated skin pathology-that is, dermatitis. Methods: The impact of the H1R invalidation on the development of skin inflammation was analyzed in a mouse model of atopic dermatitis. Results: We show that H1r(-/-) mice developed reduced allergen-specific skin lesions. Lack of H1R expression on dendritic cells (DCs) led to diminished IL-12, upregulated IL-23, and IL-6 production upon allergen stimulation. H1R engagement on dendritic cells was necessary for DC activation and subsequent priming of effector IFN-gamma(+)CD8(+) T cells. We demonstrate here that H1R blockade on DCs promotes generation of noneffector IL-17(+)CD8(+) T cells that are unable to initiate the skin inflammation. Conclusion: Our data identify that histamine signaling through the H1R on DCs is an important early event conditioning the quality of the skin effector immune response. (J Allergy Clin Immunol 2011;127:943-53.)