Mast cell-derived IL-13 downregulates IL-12 production by skin dendritic cells to inhibit the Th1 response to cutaneous antigen exposure.

ABSTRACT Background Atopic dermatitis (AD) is characterized by a skin barrier defect, aggravated by mechanical injury inflicted by scratching, a Th2-dominated immune response and susceptibility to viral skin infections normally restrained by a Th1 response. The signals leading to a Th2-dominated immune response in AD are not completely understood. Objective Determine the role of IL-13 in the initiation of the Th cell response to cutaneously encountered antigens. Methods WT, Il13-/,- Il1rl1-/-, Il4ra-/- and mice with selective deficiency of IL-13 in mast cells (MCs) were studied, dendritic cells (DCs) purified from the draining lymph nodes (dLNs) of tape-stripped and ovalbumin (OVA)-sensitized skin were examined for their ability to polarize naive OVA-TCR transgenic CD4+ T cells. Cytokine expression was examined by RT-qPCR, intracellular flow cytometry and ELISA. Contact hypersensitivity (CHS) to dinitrofluorobenzene (DNFB) was examined. Results Tape stripping caused IL-33-driven upregulation of Il13 expression by skin MCs. MC-derived IL-13 acted on DCs from dLNs of OVA-sensitized skin to selectively suppress their ability to polarize naive OVA-TCR transgenic CD4+ T cells into interferon-γ (IFN-γ) secreting cells. MC-derived IL-13 inhibited the Th1 response in CHS to DNFB. IL-13 suppressed IL-12 production by mouse skin-derived DCs in vitro and in vivo. Scratching upregulated IL13 expression in human skin, and IL-13 suppressed the capacity of lipopolysaccharide-stimulated human skin DCs to express IL-12 and promote IFN-γ secretion by CD4+ T cells. Conclusion Release of IL-13 by cutaneous MCs in response to mechanical skin injury inhibits the Th1 response to cutaneous antigen exposure in AD.