Abstract: SA-OR93
Lymphangiogenesis Regulates the Differentiation and Function of Th1 Cells in Experimental Anti-Glomerular Basement Membrane (GBM) Crescentic Glomerulonephritis (cGN)
Session Information
- Glomerular Diseases: From Multiomics to Mechanisms
November 04, 2023 | Location: Room 103, Pennsylvania Convention Center
Abstract Time: 05:15 PM - 05:24 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
Authors
- Hu, Danni, Division of Nephrology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan, China
- Pei, Guangchang, Division of Nephrology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan, China
- Xu, Gang, Division of Nephrology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan, China
- Zeng, Rui, Division of Nephrology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan, China
Background
Increasing evidence has shown the critical role of Th1 cells in the pathogenesis of anti-GBM cGN, however, the underlying mechanism is unclear. Our previous study has reported lymphangiogenesis regulate the activation and polarization of T cells in chronic kidney diseases. However, whether lymphatic vessel endothelial cells (LECs) controls the differentiation of Th1 cells in anti-GBM cGN remains unknown.
Methods
To address this question, we established the selective proliferating lymphatic vessel knockout mice for experimental anti-GBM cGN. Single-cell RNA sequencing, Bulk RNA sequencing and histological methods were used to investigate the immunopathological features of various renal T cells in anti-GBM cGN. Intra-renal LECs were obtained through multicolor flow cytometry and smart sequencing technology was applied to analyze the transcriptional signature of LECs.
Results
We found lymphangiogenesis is actively involved in anti-GBM cGN. Deletion of proliferated LECs protects against anti-GBM cGN. Most significantly, the proportion of Th1 cells in the LECs knockout mice decreased with a significantly down-regulated interferon response. Smart sequencing analysis on LECs revealed that the expression of IFN-γ which promotes Th1 differentiation increased significantly in anti-GBM cGN group, but decreased in LECs knockout group. At the same time, the function of cDC1, the main effector cell to induce Th1 differentiation, changes from pro-inflammatory activation to regulation of tolerance. In addition, the transcriptional expression profiles of T cells enriching the signal pathways related to Th1, Th2 and Th17 cell differentiation were inhibited after LECs knockout. It is further demonstrated that LECs also produce chemokines CCL5 and XCL1 to recruit cDC1, which was reversed by LECs knockout in anti-GBM cGN.
Conclusion
Our studies reveal functionally crosstalk between LECs and T cells in anti-GBM cGN. LECs directly or indirectly involved in the chemotaxis, differentiation and activation of Th1 cells. In conclusion, the findings uncover a previously unidentified role for lymphangiogenesis in progressive immune-mediated kidney disease, implying that LECs-Th1 cell axis can be a novel and effective immunotherapy target for anti-GBM cGN.