Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: Distinct roles

Julia Menke, Julie A. Lucas, Geraldine C. Zeller, Mary E. Keir, Xiao R. Huang, Naotake Tsuboi, Tanya N. Mayadas, Han Y. Lan, Arlene H. Sharpe, Vicki Rubin Kelley

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67 Citations (Scopus)


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 celland macrophage (Mφ)-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.

Original languageEnglish
Pages (from-to)7466-7477
Number of pages12
JournalJournal of Immunology
Issue number11
Publication statusPublished - 01-12-2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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