Background: Recent findings have shown that the surface expression of the high-affinity receptor for IgE (FcϵRI) on human CD1a⁺ Langerhans cells (LC) and related dendritic cells (DC) in the skin, despite a constant intracellular expression of its ⍺ chain (FcϵRI⍺), is highly up-regulated in atopic dermatitis. Moreover, this surface expression correlates with the IgE serum level, strongly suggesting yet-to-be-defined common signals in the regulation of FcϵRI display on LC/DC and IgE synthesis. Objectives: In this study we examined the influence of different cytokines on the expression of FcϵRI on in vitro–generated CD1a⁺ LC/DC. Methods: CD34⁺ precursor cells were isolated from cord blood with use of high-gradient magnetic cell sorting, cultured with GM-CSF, TNF-⍺, IL-4, or IFN-γ, and surface and cytoplasmic staining for flow cytometry were performed. Results: IL-4 strongly enhanced the generation of CD1a⁺ LC/DC and also up-regulated the expression of the skin-homing structures E-cadherin and cutaneous lymphocyte antigen. In contrast, IFN-γ was found to suppress the E-cadherin expression and to be a strong antagonist of IL-4 by inhibiting the production of CD1a⁺ cells. Most important, IL-4 induced the cytoplasmic expression of FcϵRI⍺ in CD1a⁺ LC/DC but not its surface expression. This up-regulation was antagonized by IFN-γ. Conclusion: IL-4 is not only a key cytokine in the regulation of IgE but also induces the expression of its receptor binding chain as well as up-regulation of skin homing molecules on LC/DC. Expression of these structures during generation of LC/DC reflects the in vivo situation encountered in LC. (J Allergy Clin Immunol 2000;105:150-6.)