Endothelial Cells Regulate Proinflammatory T Cell Responses in Large Vessel Vasculitis Via NOTCH-NOTCH Ligand Interactions

Zhenke Wen¹, Hui Zhang¹, Joyce Liao², Gerald Berry³, Lindsy J. Forbess⁴, Michael Weissman⁵, Jorg Goronzy¹ and Cornelia M. Weyand⁶, ¹Medicine: Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ²Byers Eye Institute at Stanford, Stanford University, Palo Alto, CA, ³Pathology, Stanford University School of Medicine, Stanford, CA, ⁴Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ⁵Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ⁶Medicine, Stanford University School of Medicine, Stanford, CA

Meeting: ACR/ARHP Annual Meeting 2015

Date of first publication: September 29, 2015

Keywords: endothelial cells and large vessel vasculitis, T cells

Session Information

Date: Tuesday, November 10, 2015

Title: Vasculitis III

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: In large vessel vasculitis (LVV), inflammatory infiltrates typically accumulate within the mural layers of the aorta and its major branches and are composed of macrophages, T cells and dendritic cells. Before T cells can reach the site of inflammation, they have to extravagate from the circulation and interact with endothelial cells (EC). How this interaction shapes disease-relevant T cell functions is not understood.

Methods: Peripheral blood T cells were isolated from healthy donors and patients with aortitis who had a positive biopsy for GCA and cultured on EC monolayers that had previously been treated with the patient’s serum for 24 hours. Four days later CD4 T cells were analyzed for the expression of the lineage-determining transcription factors RORγt, T-bet, GATA-3 and FoxP3 and for intracellular cytokine stores.

Results: Serum pretreated EC changed the differentiation program of the interacting T cells and upregulated RORγt (P=0.03) and T-bet (P<0.001), while suppressing GATA-3 (P<0.001) and FoxP3 (P<0.001). The shift in transcription factor expression was associated with the expansion of Th1 and Th17 cells and the loss of Th2 and Treg cells. This effect required serum pretreatment and was not observed if the serum derived from patients with the inflammatory disease rheumatoid arthritis (P>0.1). To identify underlying molecular pathways, the T cell-EC cocultures were treated with small molecule inhibitors to block intracellular signaling networks. The γ-secretase inhibitor DAPT, which disrupts the NOTCH signaling pathway, was able to abrogate the shift in T cell differentiation (P<0.001). Flow cytometry confirmed that GCA T cells express the NOTCH receptor NOTCH1 and GCA serum-treated EC express the NOTCH ligand Jagged1 (P=0.003).

Conclusion: In patients with GCA, EC acquire expression of Jagged1, which enables such cells to actively communicate with T cells and interfere with their differentiation program. Signal-sending Jagged1⁺ EC bias T cell differentiation towards proinflammatory effector functions, including the production of IFN-γ and IL-17 and loss of anti-inflammatory Tregs. In LVV, EC not only facilitate the entrance into the arterial wall, they actively participate in swaying T cell immunity.

Disclosure: Z. Wen, None; H. Zhang, None; J. Liao, None; G. Berry, None; L. J. Forbess, None; M. Weissman, None; J. Goronzy, None; C. M. Weyand, None.

To cite this abstract in AMA style:

Wen Z, Zhang H, Liao J, Berry G, Forbess LJ, Weissman M, Goronzy J, Weyand CM. Endothelial Cells Regulate Proinflammatory T Cell Responses in Large Vessel Vasculitis Via NOTCH-NOTCH Ligand Interactions [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/endothelial-cells-regulate-proinflammatory-t-cell-responses-in-large-vessel-vasculitis-via-notch-notch-ligand-interactions/. Accessed .

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