Neurokinin-1 Receptor Signaling Is Required for Efficient Ca2+ Flux in T-Cell-Receptor-Activated T Cells
Adrian E. Morelli,
Tina L. Sumpter,
Darling M. Rojas-Canales,
Mohna Bandyopadhyay,
Zhizhao Chen,
Olga Tkacheva,
William J. Shufesky,
Callen T. Wallace,
Simon C. Watkins,
Alexandra Berger,
Christopher J. Paige,
Louis D. Falo, Jr.,
Adriana T. Larregina
Affiliations
Adrian E. Morelli
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, School of Medicine Pittsburgh, PA, USA
Tina L. Sumpter
Department of Immunology, University of Pittsburgh, School of Medicine Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
Darling M. Rojas-Canales
Flinders University, College of Medicine and Public Health, Adelaide, SA, Australia
Mohna Bandyopadhyay
Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
Zhizhao Chen
Hubei Key Laboratory of Medical Technology on Transplantation, Transplant Center, Institute of Hepatobiliary Diseases, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
Olga Tkacheva
Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
William J. Shufesky
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
Callen T. Wallace
Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; The McGowan Center for Regenerative Medicine, Pittsburgh, PA, USA
Simon C. Watkins
Department of Immunology, University of Pittsburgh, School of Medicine Pittsburgh, PA, USA; Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; The McGowan Center for Regenerative Medicine, Pittsburgh, PA, USA
Alexandra Berger
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada
Christopher J. Paige
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada
Louis D. Falo, Jr.
Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; The McGowan Center for Regenerative Medicine, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, USA; The University of Pittsburgh Clinical and Translational Science Institute, Pittsburgh, PA, USA; The UPMC Hillman Cancer Center, Pittsburgh, PA, USA
Adriana T. Larregina
Department of Immunology, University of Pittsburgh, School of Medicine Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; The McGowan Center for Regenerative Medicine, Pittsburgh, PA, USA; Corresponding author
Summary: 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. : 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. Keywords: neurokinin-1 receptor, T cell receptor, G-protein-coupled receptors, Ca2+ flux, Gαq/11, substance P, hemokinin-1, T cell activation, T cell bias, T cell survival
