IMMUNOBIOLOGY Neurokinin - 1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL - 12

The immune and nervous systems are far more interconnected than originally thought. They sense and respond to danger, release shared mediators, and generate and store memory. Based on these similarities, the immune system has been considered “the sixth sense”. Our knowledge on neuroimmunology comes mainly from studies analyzing the effects of immune cells on the central nervous system, with limited information regarding the immune-regulatory mechanisms of the peripheral nervous system. As professional antigen (Ag)–presenting cells (APCs) of the immune system, dendritic cells (DCs) play crucial roles in induction of T-cell immunity and tolerance. Accordingly, the possibility of administering therapeutic DCs to regulate immunity in an Agspecific manner has revolutionized the field of translational immunology over the past 2 decades. Numerous methodologies have been developed to generate DCs ex vivo that mimic the functions of tissue-resident or -recruited DCs, with the intent to activate or suppress specific immunity. In vitro–generated and/or –engineered therapeutic DCs are highly desired for positive vaccination against intracellular pathogens or tumors, and for negative immunization protocols to treat autoimmune disorders or transplant rejection, respectively. Considering the importance of neuropeptides in the regulation of immunity, the lack of information regarding their role on the biology of therapeutic DCs is surprising. Substance P (SP), a prototypical proinflammatory neuropeptide of the tachykinin family secreted by d-fibers, is crucial for induction of the neuroinflammatory reflex and perpetuation of inflammation and autoimmunity. Likewise, the more recently described hemokinin-1 (HK-1) has strong proinflammatory effects. These tachykinins exert their effects by binding with high affinity to the neurokinin-1 receptor (NK1R), a 7 transmembrane domain G-protein–coupled receptor expressed as either a full-length or a nonfunctional truncated isoform. In a previous publication, we demonstrated that skin Langerhans cells and bone marrow (BM)–derived DCs (BMDCs) express functional NK1R, and respond to NK1R agonists with increased cell survival and migration to skin-draining lymph nodes (sDLNs). These immunologic effects suggest that NK1R agonists could be used as adjuvants for enhancing the efficiency of DC vaccines. Here, we demonstrate that conditioning BMDCs with NK1R agonists, leads to their maturation and abrogation of interleukin-10 (IL-10) release without inducing IL-12p70 secretion. Inhibition of IL-10 occurs via blockade of the CREB1/TORC2 signaling pathway. Following subcutaneous administration as a cellular vaccine, Ag-loaded and NK1R-signaled BMDCs (Ag-NK1R-DCs) homed in sDLNs, promoting inflammation and potent CD4 T helper (Th1) and CD8 (Tc1)– mediated immunity. Generation of type 1 immunity in vivo required IL-12p70 from host lymph node (LN) DCs, including resident and recruited inflammatory DCs. These 2 DC subsets were activated in situ subsequently to the homing in the sDLNs of the injected BMDCs. Mechanistic studies demonstrated that the reduced levels of IL-10 produced by NK1R-DCs licensed IL-12 secretion by host DCs resulting in potent type 1 immunity.