Wen Zhenke, Shen Yi, Berry Gerald, Shahram Farhad, Li Yinyin, Watanabe Ryu, Liao Yaping Joyce, Goronzy Jörg J, Weyand Cornelia M
Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Transl Med. 2017 Jul 19;9(399). doi: 10.1126/scitranslmed.aal3322.
Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (T1) and T17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating the expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients' blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway, and differentiate into T1 and T17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.
大动脉外膜中的微血管网络控制着炎症细胞进入内膜层(中膜和内膜),从而保护主动脉及其主要分支的免疫特权。在自身免疫性血管炎巨细胞动脉炎(GCA)中,CD4辅助性T细胞1(T1)和T17细胞侵入主动脉壁和大弹性动脉壁,形成组织破坏性肉芽肿。疾病微环境是否为致血管炎的T细胞提供指导性线索尚不清楚。我们报告称,外膜微血管内皮细胞(mvECs)通过上调Notch配体Jagged1的表达来发挥免疫调节功能。血管内皮生长因子(VEGF)大量存在于GCA患者的血液中,可诱导Jagged1表达,使mvECs能够通过Notch-mTORC1(雷帕霉素复合物1的哺乳动物靶点)途径调节效应T细胞的诱导。我们发现,GCA患者循环中的CD4 T细胞已脱离静止状态,通过Notch途径积极发出信号,并分化为T1和T17效应细胞。在大血管血管炎的体内模型中,外源性VEGF作为一种有效的放大器,招募并激活致血管炎的T细胞。因此,全身性VEGF利用内皮细胞Jagged1触发异常的Notch信号,使CD4 T细胞的反应性产生偏差,并诱导致病性效应功能。外膜微血管网络作为一种指导性的组织微环境,可被用于针对大血管血管炎中的致血管炎免疫。