Hemokinin-1 and Substance P provide adjuvancy for T cell activation and survival necessary for innate and adaptive cellular immune responses

Abstract

Abstract Chronic inflammatory and autoimmune disorders rely on the generation of efficient T cell responses. The pro-inflammatory neuropeptides, hemokinin-1 (HK-1) and substance P (SP) potentiate cellular immunity by signaling via the neurokinin-1 receptor (NK1R) expressed in leukocytes, including T cells. HK-1 is secreted by leukocytes while SP is released by sensory nerves and tissue resident cells. The role of NK1R signaling in the effector functions of T cells remains ill understood. We investigated the effects of signaling via the NK1R in the population of activated T-cells. In vitro, we compared the effects of HK-1 and SP on the survival and effector functions of wild type (WT) and NK1RKO CD4 and CD8 T cells. In vivo, we compared the effect of NK1R-signaling on T cells by using a delayed-type hypersensitivity (DTH) model in hosts with selective deletion of the NK1R in T cells. We demonstrate that NK1R-signaling is necessary for the generation, and maintenance of the survival and effector functions of CD4 and CD8 T cells. T cells secreted HK-1 and SP to promote self-activation and survival. Signaling via the NK1R resulted in Ca2+-influx in T cells, and that effect was impaired in NK1RKO T cells. Downstream, NK1R signaling activated the Ca2+-dependent NFAT1 and NFAT2 pathways, with the consequent increases in the synthesis and secretion of IL-2 that sustained T cell survival. In addition, NK1R-signaling stimulated the MAPK (c-Fos and c-Jun) and NF-kB pathways resulting in T cell activation. In vivo, DTH assays were significantly compromised in mice with selective deletion of NK1R+ T cells compared to WT. Our results elucidate the role and mechanisms of specific NK1R-T cell signaling in the generation and maintenance of potent T cell responses.