Abstract: TH-PO0403
Clonal Lineage Tracing Reveals Dynamic KIR Expression and Kidney Trafficking of Circulating KIR+CD8+T Cells in Lupus Nephritis
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Xia, Xi, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Chen, Wei, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Cantor, Harvey, Department of Cancer Immunology & Virology, Dana Farber Cancer Institute, Boston, Massachusetts, United States
- Azzi, Jamil R., Harvard Medical School Department of Medicine, Boston, Massachusetts, United States
Background
KIR+CD8+T cells have been identified as a regulatory subset with suppressive function, but their clonal expansion, KIR expression stability, and ability to migrate to the kidney have not been directly investigated in human LN.
Methods
We performed single-cell RNA/TCR sequencing on paired blood and kidney samples from 7 LN patients. A total of 192 unique TCR clonotypes were identified. Clonal sharing between KIR+ and KIR- compartments and between blood and kidney was analyzed. IMQ-induced lupus-like mouse model was used for in vivo functional validation, including anti-Ly49F depletion and FL9-TCR adoptive transfer, with assessment of renal histopathology (IgG deposition), serum autoantibodies (anti-dsDNA), and proteinuria.
Results
Single-cell RNA/TCR sequencing of paired blood and kidney samples from LN patients revealed striking oligoclonal expansion of circulating KIR+CD8+T cells, with a small number of expanded clonotypes dominating the repertoire and a single large clonotype comprising a substantial fraction of all KIR+CD8+T cells. Notably, a substantial proportion of clonotypes were shared between KIR+ and KIR-compartments demonstrating that KIR is dynamically regulated and does not define a distinct functional state. Direct clonal tracking using paired blood and kidney samples provided unequivocal evidence of clonal trafficking from circulation to the kidney.
In vivo functional validation was performed in an IMQ-induced lupus-like mouse model. Depletion of Ly49+CD8+T cells—the murine homolog of human KIR+CD8+T cells—using anti-Ly49F antibody significantly exacerbated disease, as evidenced by enhanced glomerular IgG deposition on renal pathology and elevated serum anti-dsDNA antibody levels. Conversely, adoptive transfer of FL9-TCR transgenic CD8+T cells ameliorated lupus-like manifestations, reducing proteinuria, glomerular immune complex deposition, and autoantibody titers. Together, these gain- and loss-of-function experiments establish a protective causal role for this CD8+T cell subset in lupus nephritis.
Conclusion
Circulating KIR+CD8+T cells in LN exhibit extreme oligoclonal expansion, dynamic KIR expression, and the capacity to migrate to the kidney and in vivo mouse models confirm their protective function.