Neurokinin-1 Receptor Signaling Is Required for Efficient Ca2+ Flux in T-Cell-Receptor-Activated T Cells

• Published in: Cell reports (Cambridge) 2020-03, Vol.30 (10), p.3448-3465.e8
• Main Authors: Morelli, Adrian E., Sumpter, Tina L., Rojas-Canales, Darling M., Bandyopadhyay, Mohna, Chen, Zhizhao, Tkacheva, Olga, Shufesky, William J., Wallace, Callen T., Watkins, Simon C., Berger, Alexandra, Paige, Christopher J., Falo, Louis D., Larregina, Adriana T.
• Format: Article
• Language: English
• Subjects: Ca2+ flux; G-protein-coupled receptors; Gαq/11; hemokinin-1; neurokinin-1 receptor; substance P; T cell activation; T cell bias; T cell receptor; T cell survival
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.02.054

Efficient Ca2+ flux induced during cognate T cell activation requires signaling the T cell receptor (TCR) and unidentified G-protein-coupled receptors (GPCRs). T cells express the neurokinin-1 receptor (NK1R), a GPCR that mediates Ca2+ flux in excitable and non-excitable cells. However, the role of the NK1R in TCR signaling remains unknown. We show that the NK1R and its agonists, the neuropeptides substance P and hemokinin-1, co-localize within the immune synapse during cognate activation of T cells. Simultaneous TCR and NK1R stimulation is necessary for efficient Ca2+ flux and Ca2+-dependent signaling that sustains the survival of activated T cells and helper 1 (Th1) and Th17 bias. In a model of contact dermatitis, mice with T cells deficient in NK1R or its agonists exhibit impaired cellular immunity, due to high mortality of activated T cells. We demonstrate an effect of the NK1R in T cells that is relevant for immunotherapies based on pro-inflammatory neuropeptides and its receptors. [Display omitted] •T cells express the neurokinin 1 receptor (NK1R) and synthesize its agonists•The NK1R and its agonists co-localize in or near the T cell: APC immune synapse•The NK1R promotes optimal Ca2+ flux and survival of TCR-activated T cells•Lack of the NK1R or its agonists results in deficient Th1-/Th17-biased immunity The neurokinin 1 receptor (NK1R) induces Ca2+ flux in excitable cells. Here, Morelli et al. show that NK1R signaling in T cells promotes optimal Ca2+ flux triggered by TCR stimulation, which is necessary to sustain T cell survival and the efficient Th1- and Th17-based immunity that is relevant for immunotherapies based on pro-inflammatory neuropeptides.