Neurokinin-1 receptor stimulated dendritic cell vaccines downregulate IL-10 and license host inflammatory dendritic cells to bias Th1 immunity (P4236)

Abstract

Abstract Substance-P (SP) is a neuropeptide that stimulates immunity by binding to the neurokinin-1 receptor (NK1R). As professional Ag presenting cells, dendritic cells (DC) are unique activators of naïve T cells. DC express functional NK1R, indicating that NK1R agonists may influence their T cell-stimulatory function. Relevant studies analyzing the relationship between neuropeptides and DC function are lacking. Here, we demonstrate that conditioning bone marrow derived DC (BMDC) with NK1R agonists leads to maturation and abrogation of IL-10 without inducing secretion of IL-12p70. Mechanistic analyses in vitro demonstrated that NK1R signaling blocks the CREB1/TORC2 pathway to inhibit the Il-10 promoter. Following subcutaneous administration as a cellular vaccine, Ag-loaded and NK1R-signaled BMDC homed to skin draining lymph nodes (sDLN), initiating inflammation and Th1 and Tc1 immunity in vivo. This type-1 immunity required IL-12p70 secreted in sDLN by host DC, including LN-resident, and recruited inflammatory DC. Utilizing CCR7KO BMDC and IL-12p35KO mice, we elucidated that endogenous DC subsets were activated in situ by NK1R-signaled-BMDC homing to sDLN. Moreover, reduced levels of IL-10 by NK1R signaled BMDC licensed IL-12 secretion by host DC and mediated type-1 immunity. Our data demonstrate that NK1R-signaling promotes immunostimulatory DC and provide a relevant insight into the mechanisms employed by neuromediators to regulate the outcome of cellular immune responses.