Mast cell-derived IL-13 downregulates IL-12 production by skin dendritic cells to inhibit the T_H1 cell response to cutaneous antigen exposure.

Abstract

Atopic dermatitis (AD) is characterized by a skin barrier defect aggravated by mechanical injury inflicted by scratching, a T_H2 cell-dominated immune response, and susceptibility to viral skin infections that are normally restrained by a T_H1 cell response. The signals leading to a T_H2 cell-dominated immune response in AD are not completely understood. Our aim was to determine the role of IL-13 in initiation of the T_H cell response to cutaneously encountered antigens. Wild-type, Il13^-/-, Il1rl1^-/-, and Il4ra^-/- mice, as well as mice with selective deficiency of IL-13 in mast cells (MCs) were studied; in addition, dendritic cells (DCs) purified from the draining lymph nodes 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 reverse-transcriptase quantitative PCR, intracellular flow cytometry, and ELISA. Contact hypersensitivity to dinitrofluorobenzene was examined. Tape stripping caused IL-33-driven upregulation of Il13 expression by skin MCs. MC-derived IL-13 acted on DCs from draining lymph nodes of OVA-sensitized skin to selectively suppress their ability to polarize naive OVA-TCR transgenic CD4⁺ T cells into IFN-γ-secreting cells. MC-derived IL-13 inhibited the T_H1 cell response in contact hypersensitivity to dinitrofluorobenzene. 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 LPS-stimulated human skin DCs to express IL-12 and promote IFN-γ secretion by CD4⁺ T cells. Release of IL-13 by cutaneous MCs in response to mechanical skin injury inhibits the T_H1 cell response to cutaneous antigen exposure in AD.