AbstractEpidermal nerves are closely associated with Langerhans cells (LC) and may be able to release factors, such as calcitonin gene‐related peptide and epinephrine, that affect LC function. LC and the LC‐like cell line XS106 express mRNA for the pituitary adenylate cyclase‐activating polypeptide (PACAP) receptors VPAC1 and VPAC2. We examined whether PACAP regulates cutaneous immunity. Intradermal administration of PACAP prior to application of a contact sensitizer at the injected site inhibited the induction of contact hypersensitivity. Pretreatment of murine epidermal cells enriched for LC content (∼12% LC) with PACAP inhibited their ability to elicit delayed‐type hypersensitivity in previously immunized mice. In vitro, PACAP suppressed the ability of both murine epidermal cells and highly purified LC (∼95%) to present antigen to a T cell clone and hybridoma. Furthermore, in LC and the XS106 cell line, PACAP inhibited the LPS/GM‐CSF‐induced stimulation of IL‐1β secretion and augmented IL‐10 production. PACAP also down‐regulated CD86 expression in LPS/GM‐CSF‐stimulated XS106 cells. The immunosuppressive effects of PACAP may be due to modulation ofcytokine production and CD86 expression.