Agonistic signaling via the neurokinin 1 receptor and CD40 have a synergistic effect to promote dendritic cell survival and potent CTL responses (135.56)

Abstract

Abstract Immune competent organs are richly innervated and pro-inflammatory neuropeptides released by nerve endings favor the initiation of innate and adaptive immune responses. By binding the neurokinin 1 receptor (NK1R), the pro-inflammatory neuropeptide substance P promotes immune cell survival and potent cellular immunity. Dendritic cells (DCs) express surface NK1R and the priming of T cell responses requires Ag presentation by DCs able to withstand apoptotic signaling. We hypothesized that signaling DCs via the NK1R prevents apoptosis of DCs favoring sustained DC-T cell contact and robust CTL responses. Using murine bone marrow-derived DCs (BMDCs) cultured with the NK1R agonist [Sar9Met(02)11]-SP (SarSP-DCs), we demonstrate that signaling via the NK1R utilizes the PI3K-Akt pathway to prolong the expression of anti-apoptotic molecules. Additionally, SarSP-DCs showed increased expression of surface CD40. Adoptive transfer of Ag-loaded SarSP-DCs showed enhanced longevity in local draining lymph nodes vs. control DCs, which was a result of a combination of signaling via the NK1R and CD40 molecules. Importantly, SarSP-DCs elicited potent CTL responses compared to control DCs. We conclude that agonistic signaling via the NK1R and CD40 have a synergistic effect that enhances DC survival and favors the generation of potent CTL responses. Supported by NIH grant: R01 CA100893 (ATL)