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* Laboratory of Molecular Autoimmune Disease, Renal Division, and
Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115;
Department of Medicine, University of Hong Li Ka Shing Facility of Medicine, Hong Kong, China; and
Department of Pathology, Center of Excellence in Vascular Biology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115
The programmed death 1/programmed death 1 ligand (PD-L) pathway is instrumental in peripheral tolerance. Blocking this pathway exacerbates experimental autoimmune diseases, but its role in autoimmune kidney disease has not been explored. Therefore, we tested the hypothesis that the programmed death 1 ligands (PD-L1 and PD-L2), provide a protective barrier during T cell- and macrophage (M
)-dependent autoimmune kidney disease. For this purpose, we compared nephrotoxic serum nephritis (NSN) in mice lacking PD-L1 (PD-L1–/–), PD-L2 (PD-L2–/–), or both (PD-L1/L2–/–) to wild-type (WT) C57BL/6 mice. Kidney pathology, loss of renal function, and intrarenal leukocyte infiltrates were increased in each PD-L–/– strain as compared with WT mice. Although the magnitude of renal pathology was similar in PD-L1–/– and PD-L2–/– mice, our findings suggest that kidney disease in each strain is regulated by distinct mechanisms. Specifically, we detected increased CD68+ cells along with elevated circulating IgG and IgG deposits in glomeruli in PD-L2–/– mice, but not PD-L1–/– mice. In contrast, we detected a rise in activated CD8+ T cells in PD-L1–/– mice, but not PD-L2–/– mice. Furthermore, since PD-L1 is expressed by parenchymal and hemopoietic cells in WT kidneys, we explored the differential impact of PD-L1 expression on these cell types by inducing NSN in bone marrow chimeric mice. Our results indicate that PD-L1 expression on hemopoietic cells, and not parenchymal cells, is primarily responsible for limiting leukocyte infiltration during NSN. Taken together, our findings indicate that PD-L1 and PD-L2 provide distinct negative regulatory checkpoints poised to suppress autoimmune renal disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants R01 DK 52369 (to V.R.K.) and PO1 AI 56299 (to A.H.S.) and grants from Genzyme Renal Innovations Program (to V.R.K.). J.M. and G.Z. received support from the Deutsche Forschungsgemeinschaft (Grants ME-3194/1-1 and ZE-711/1, respectively). J.L. was supported by Ruth L. Kirschstein National Research Service Award F32 DK078416-01.
2 J.M. and J.A.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Vicki Rubin Kelley, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: vkelley{at}rics.bwh.harvard.edu
4 Abbreviations used in this paper: PD-1, programmed-death 1; PD-L1, PD-1 ligand 1; PD-L2, PD-1 ligand 2; M, macrophage; NSN, nephrotoxic serum nephritis; WT, wild type; DC, dendritic cell; TEC, tubular epithelial cell; BUN, blood urea nitrogen; BM, bone marrow; mfi, mean fluorescence intensity.
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  J. A. Lucas, J. Menke, W. A. Rabacal, F. J. Schoen, A. H. Sharpe, and V. R. Kelley Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice J. Immunol., August 15, 2008; 181(4): 2513 - 2521. [Abstract] [Full Text] [PDF]
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