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.
Department of Immunology, University of Pittsburgh, School of Medicine Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
Cell Rep. 2020 Mar 10;30(10):3448-3465.e8. doi: 10.1016/j.celrep.2020.02.054.
Efficient Ca 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 Ca 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 Ca flux and Ca-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.
在同源 T 细胞激活过程中，有效的钙流需要信号转导 T 细胞受体（TCR）和未识别的 G 蛋白偶联受体（GPCR）。T 细胞表达神经激肽-1 受体（NK1R），一种 GPCR，在可兴奋和非兴奋细胞中介导钙流。然而，NK1R 在 TCR 信号转导中的作用仍然未知。我们发现，在同源 T 细胞激活过程中，NK1R 及其激动剂，神经肽物质 P 和血啡肽-1，在免疫突触内共定位。同时刺激 TCR 和 NK1R 对于有效的钙流和钙依赖性信号转导是必要的，钙依赖性信号转导维持激活的 T 细胞以及辅助 1（Th1）和 Th17 偏向的存活。在接触性皮炎模型中，缺乏 NK1R 或其激动剂的 T 细胞的小鼠表现出细胞免疫受损，这是由于激活的 T 细胞死亡率高所致。我们证明了 NK1R 在 T 细胞中的作用，这对于基于促炎神经肽及其受体的免疫疗法是相关的。
