Research ArticleInflammation

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

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Science Translational Medicine  19 Jul 2017:
Vol. 9, Issue 399, eaal3322
DOI: 10.1126/scitranslmed.aal3322

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Initiating inflammation

Giant cell arteritis (GCA) is an autoimmune disease in which immune cells infiltrate into large blood vessel walls. Wen et al. investigated whether microvascular endothelial cells (mvECs) in the adventitia, the outermost layer of large blood vessels, contributed to GCA. The authors found increased circulating plasma vascular endothelial growth factor (VEGF) linked to the expression of Jagged1, a ligand involved in Notch signaling, in GCA patient blood vessels. Patient T cells expressed Notch1 and received activating signals from Jagged1-expressing mvECs. VEGF enhanced Jagged1 expression and vessel wall inflammation when human arteries and patient peripheral blood mononuclear cells were implanted into mice. The authors discovered that adventitial mvEC Jagged1 induced the differentiation of proinflammatory effector cells, suggesting that the adventitial microvasculature may be a useful target for GCA therapies.

Abstract

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 (TH1) and TH17 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 TH1 and TH17 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.

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