Anti-Programmed Cell Death 1 Antibody Reduces CD4+PD-1+ T Cells and Relieves the Lupus-Like Nephritis of NZB/W F1 Mice
Anti-Programmed Cell Death 1 Antibody Reduces CD4+PD-1+ T Cells and Relieves the Lupus-Like Nephritis of NZB/W F1 Mice
复制标题
DOI：
10.4049/jimmunol.0901652
复制
发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Kumagai, Shunichi
中科院分区：
文献类型：
--
作者：
Kasagi, Shimpei;Kawano, Seiji;Kumagai, Shunichi
程序性细胞死亡1（PD-1）是一种免疫抑制受体，其将抑制信号转导到活化的T细胞中。尽管PD-1基因的单核苷酸多态性与系统性红斑狼疮的易感性相关，但PD-1在系统性红斑狼疮中的作用仍不清楚。在这项研究中，我们使用NZB/WF 1小鼠，狼疮样肾炎模型，检查PD-1及其配体的功能。PD-1主要在浸润肾脏的CD 4（+）T细胞上表达，并且CD 4（+）PD-1（高）T细胞比CD 4（+）PD-1（低）或CD 4（+）PD-1（-）T细胞产生更高水平的IFN-γ。用PMA/离子霉素刺激导致脾CD 4（+）PD-1（+）T细胞分泌高水平的IFN-γ、IL-10、低水平的TNF-α、微弱水平的IL-2、IL-21，并且不分泌IL-4、IL-17。体内抗PD-1 mAb治疗减少了NZB/W F1小鼠肾脏中CD 4（+）PD-1（+）T细胞的数量，并显著降低了其死亡率（p = 0.03）。相反，使用抗PD-L1 mAb阻断PD-L1可增加肾脏中CD 4（+）PD-1（+）T细胞的数量，提高血清IFN-γ、IL-10和IgG 2a ds-DNA-Ab水平，加速肾炎，并增加死亡率。我们得出结论，CD 4（+）PD-1（高）T细胞是NZB/W F1小鼠中IFN-γ产生失调的促炎细胞。免疫学杂志，2010，184：2337-2347。
Programmed cell death 1 (PD-1) is an immunosuppressive receptor that transduces an inhibitory signal into activated T cells. Although a single nucleotide polymorphism in the gene for PD-1 is associated with susceptibility to systemic lupus erythematosus, the role of PD-1 in systemic lupus erythematosus is still not well understood. In this study, we used NZB/W F1 mice, a model of lupus-like nephritis, to examine the function of PD-1 and its ligands. PD-1 was predominantly expressed on CD4(+) T cells that infiltrated the kidney, and CD4(+)PD-1(high) T cells produced higher levels of IFN-gamma than CD4(+)PD-1(low) or CD4(+)PD-1(-) T cells. Stimulation with PMA/ionomycin caused splenic CD4(+)PD-1(+) T cells to secrete high levels of IFN-gamma, IL-10, low levels of TNF-alpha, faint levels of IL-2, IL-21, and no IL-4, IL-17. In vivo anti-PD-1 mAb treatment reduced the number of CD4(+)PD-1(+) T cells in the kidney of NZB/W F1 mice and significantly reduced their mortality rate (p = 0.03). Conversely, blocking PD-L1 using an anti-PD-L1 mAb increased the number of CD4(+)PD-1(+) T cells in the kidney, enhanced serum IFN-gamma, IL-10, and IgG2a ds-DNA-Ab levels, accelerated the nephritis, and increased the mortality rate. We conclude that CD4(+)PD-1(high) T cells are dysregulated IFN-gamma-producing, proinflammatory cells in NZB/W F1 mice. The Journal of Immunology, 2010, 184: 2337-2347.