Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: Distinct roles
Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: Distinct roles
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DOI：
10.4049/jimmunol.179.11.7466
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Kelley, Vicki R.
中科院分区：
文献类型：
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作者：
Menke, Julia;Lucas, Julie A.;Kelley, Vicki R.
程序性死亡 1/程序性死亡 1 配体 (PD-L) 通路在外周耐受中发挥重要作用。阻断该途径会加剧实验性自身免疫性疾病，但其在自身免疫性肾病中的作用尚未被探索。因此，我们测试了这样的假设：程序性死亡 1 配体（PD-L1 和 PD-L2）在 T 细胞和巨噬细胞 (M phi) 依赖性自身免疫性肾病期间提供保护屏障。为此，我们比较了缺乏 PD-L1 (PD-L1(-/-))、PD-L2 (PD-L2(-/-)) 或两者 (PD-L1/L2(-/-)) 的小鼠与野生型 (WT) C57BL/6 小鼠的肾毒性血清肾炎 (NSN)。与 WT 小鼠相比，每个 PD-L-/- 品系的肾脏病理、肾功能丧失和肾内白细胞浸润均增加。尽管 PD-L1(-/-) 和 PD-L2-/- 小鼠的肾脏病理程度相似，但我们的研究结果表明，每种品系的肾脏疾病都受到不同机制的调节。具体来说，我们在 PD-L2(-/-) 小鼠中检测到 CD68(+) 细胞增加，同时循环 IgG 和肾小球中 IgG 沉积物增加，但 PD-L1(-/-) 小鼠则没有。相比之下，我们检测到 PD-L1(-/-) 小鼠中活化的 CD8(+) T 细胞增加，但 PD-L2-/- 小鼠中没有。此外，由于 PD-L1 在 WT 肾脏中由实质细胞和造血细胞表达，因此我们通过在骨髓嵌合小鼠中诱导 NSN 来探索 PD-L1 表达对这些细胞类型的差异影响。我们的结果表明，造血细胞（而不是实质细胞）上的 PD-L1 表达主要负责限制 NSN 期间白细胞浸润。总而言之，我们的研究结果表明 PD-L1 和 PD-L2 提供了独特的负调节检查点，有望抑制自身免疫性肾病。
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 phi)-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.