Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4+ T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4+ T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-? and interleukin (IL)-22 release, and increased ROR?t and Gata3 mRNA expression while decreasing T-bet expression. The CD4+ T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-?-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4+ T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-?. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.