Bai Aiping, Moss Alan, Rothweiler Sonja, Serena Longhi Maria, Wu Yan, Junger Wolfgang G, Robson Simon C
Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
Nat Commun. 2015 Nov 9;6:8819. doi: 10.1038/ncomms9819.
Interferon gamma (IFNγ)-producing CD8(+) T cells (Tc1) play important roles in immunological disease. We now report that CD3/CD28-mediated stimulation of CD8(+) T cells to generate Tc1 cells, not only increases IFNγ production but also boosts the generation of reactive oxygen species (ROS) and augments expression of CD39. Inhibition of NADPH oxidases or knockdown of gp91phox in CD8(+) T cells abrogates ROS generation, which in turn modulates JNK and NFκB signalling with decreases in both IFNγ levels and CD39 expression. CD39(+)CD8(+) T cells substantially inhibit IFNγ production by CD39(-)CD8(+) T cells via the paracrine generation of adenosine, which is operational via adenosine type 2A receptors. Increases in numbers of CD39(+)CD8(+) T cells and associated enhancements in ROS signal transduction are noted in cells from patients with Crohn's disease. Our findings provide insights into Tc1-mediated IFNγ responses and ROS generation and link these pathways to CD39/adenosine-mediated effects in immunological disease.
产生干扰素γ（IFNγ）的CD8⁺ T细胞（Tc1）在免疫性疾病中发挥重要作用。我们现在报告，CD3/CD28介导的对CD8⁺ T细胞的刺激以产生Tc1细胞，不仅增加IFNγ的产生，还促进活性氧（ROS）的生成并增强CD39的表达。抑制CD8⁺ T细胞中的NADPH氧化酶或敲低gp91phox可消除ROS的生成，这反过来又调节JNK和NFκB信号传导，导致IFNγ水平和CD39表达均降低。CD39⁺CD8⁺ T细胞通过旁分泌生成腺苷，经由2A型腺苷受体发挥作用，从而显著抑制CD39⁻CD8⁺ T细胞产生IFNγ。在克罗恩病患者的细胞中，观察到CD39⁺CD8⁺ T细胞数量增加以及ROS信号转导相关增强。我们的研究结果为Tc1介导的IFNγ反应和ROS生成提供了见解，并将这些途径与免疫性疾病中CD39/腺苷介导的效应联系起来。
