Background/Purpose: Adventitial microvascular networks (vasa vasora) control the access to the wall structure of medium and large arteries and thus guard the immune privilege of the aorta and its branches. In giant cell arteritis (GCA), CD4 T helper 1 (Th1) and Th17 cells obtain access to the arterial wall layers, where together with macrophages they form granulomatous infiltrates. Whether the small adventitial vessels have a pathogenic role in GCA is unknown.

Methods: Tissue transcriptomes were examined in tissue biopsies of patients with temporal arteritis or GCA aortitis, and genes-of-interest were confirmed by immunohistochemical staining. Unprimed CD4 T cells were collected from peripheral blood of patients with active GCA and age-matched healthy controls. Effector cell differentiation was analyzed by detecting intracellular cytokines by flow cytometry or immunohistochemistry. Microvascular endothelial cell (mvEC)-T cell interactions were studied in an ex vivo and in vivo system. Relevant signaling pathways were identified by iRNA technology (Notch1, Raptor), small molecule inhibitors (NOTCH and mTORC1 inhibitors) and monoclonal antibodies

Results:

Microvascular endothelial cells (mvEC) in the adventitia of GCA-affected temporal arteries and aortas expressed abundant Jagged1, a ligand for the cell-fate-regulating receptor Notch1. Patients with active GCA had high frequencies of Notch1+ CD4 T cells, which had left the quiescent state and acquired effector cell characteristics. Jagged1-expressing mvEC were able to instruct CD4 T cells to enter differentiation and commit to Th1 and Th17 differentiation. In vivo, upregulation of Jagged1 on adventitial microvessels intensified the inflammatory activity of the vasculitogenic lesions by increasing the frequency of tissue-residing IFN-γ–producing effector cells. Jagged1-induced T cell instruction was dependent on the mTORC1 signaling pathway; commitment to either the Th1 or the Th17 lineage was sensitive to mTORC1 inhibitors.

Conclusion: Adventitial microvessels form an instructive tissue niche, that protects medium and large arteries from inflammatory attack. In GCA, this immune-protective mechanism fails and Jagged1-expressing mvEC stimulate and instruct Notch1+ CD4 T cells. This signal is sufficient for CD4 T cells to invade into the tissue site and acquire pathogenic effector functions. Vasculitogenic functions depend on the mTORC1 signaling pathway. Overall, these findings identify multiple actionable steps in the pathogenesis of GCA

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-microvascular-niche-instructs-pathogenic-t-cells-in-medium-and-large-vessel-vasculitis/