Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis

Zhang, Hui; Watanabe, Ryu; Berry, Gerald J.; Vaglio, Augusto; Liao, Yaping Joyce; Warrington, Kenneth J.; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1073/pnas.1616848114

Cited by 192 publications

(223 citation statements)

References 66 publications

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“…2). The role of T cells in GCA is confirmed by the recent study from [80] demonstrating a breakdown of the tissue-protective Programmed death1/Programmed death-ligand 1 (PD1/PD-L1) checkpoint. Engagement of PD-L1 with its receptor PD-1 on T cells inhibits TCR-mediated activation of IL-2 production and T cell proliferation [81].…”

Section: Cd4 + T Cells Play Central Roles In the Function Of The Immumentioning

(Expert classified)

New insights into the pathogenesis of giant cell arteritis

Ciccia

Rizzo

Ferrante

et al. 2017

Autoimmunity Reviews

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Section: Cd4 + T Cells Play Central Roles In the Function Of The Immumentioning

(Expert classified)

New insights into the pathogenesis of giant cell arteritis

Ciccia

Rizzo

Ferrante

et al. 2017

Autoimmunity Reviews

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“…To directly examine the disease-amplifying effects of VEGF in vivo, we induced vasculitis in NOD-nonobese diabetic- scid IL-2Rγ null (NSG) mice engrafted with human axillary arteries and reconstituted with PBMCs from patients with active GCA (26, 42). This model system recapitulates T cell-dependent vasculitis in human arteries.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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 the 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 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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“…The density of PD-L1 on the surface of antigen-presenting cells is therefore a key element in setting the threshold for the PD-1 immune checkpoint (37). PD-L1 expression is regulated by multiple signaling pathways and transcriptional and epigenetic factors (34,35).…”

Section: Resultsmentioning

confidence: 99%