Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection
Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection
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DOI：
10.1111/j.1365-2567.2011.03406.x
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发表时间：
2011-05-01
期刊：
影响因子：
6.4
通讯作者：
Cerban, Fabio M.
中科院分区：
文献类型：
--
作者：
Dulgerian, Laura R.;Garrido, Vanina V.;Cerban, Fabio M.
与程序性死亡1（PD-1）结合的程序性死亡配体1（PD-L1）和2（PD-L2）参与了慢性病毒感染和癌症期间的外周耐受和免疫逃逸机制。然而，这些分子在克氏锥虫感染中的作用还没有报道。我们研究了PD-L1和PD-L2在T. cruzi感染及其在巨噬细胞（M phi）免疫调节特性中的β-淀粉酶/诱导型一氧化氮合酶（iNOS）平衡中的重要性。在这项工作中，我们已经证明了PD-1/PD-L通路的表达在T.克氏杆菌感染对腹膜腔M phi s的影响。T. Cruzi感染的小鼠抑制T细胞增殖，当加入抗PD-1和抗PD-L1抗体时，T细胞增殖恢复。然而，抗PD-L2抗体治疗没有重新建立T细胞增殖。PD-L2对感染小鼠腹膜细胞的阻断作用显示，iNOS表达和一氧化氮（NO）产生减少，而PD-L2表达和活性增加。此外，白细胞介素-10的产生增加，而干扰素-γ的产生减少。结果，这种微环境增强了寄生虫的增殖。相反，PD-1和PD-L1阻断可增加T.克氏病毒感染的小鼠此外，PD-L2基因敲除感染的小鼠显示寄生虫血症和谷胱甘肽酶活性增加，NO产生减少。综上所述，我们的结果表明，PD-L2参与T.在对抗寄生虫的免疫应答中具有保护作用的克氏感染。
P>The programmed death ligands 1 (PD-L1) and 2 (PD-L2) that bind to programmed death 1 (PD-1) have been involved in peripheral tolerance and in the immune escape mechanisms during chronic viral infections and cancer. However, there are no reports about the role of these molecules during Trypanosoma cruzi infection. We have studied the role of PD-L1 and PD-L2 in T. cruzi infection and their importance in arginase/inducible nitric oxide synthase (iNOS) balance in the immunomodulatory properties of macrophages (M phi). In this work, we have demonstrated that expression of the PD-1/PD-L pathway is modified during T. cruzi infection on M phi s obtained from peritoneal cavity. The M phi s from T. cruzi-infected mice suppressed T-cell proliferation and this was restored when anti-PD-1 and anti-PD-L1 antibodies were added. Nevertheless, anti-PD-L2 antibody treatment did not re-establish T-cell proliferation. PD-L2 blockade on peritoneal cells from infected mice showed an increase in arginase expression and activity and a decrease in iNOS expression and in nitric oxide (NO) production. Additionally, interleukin-10 production increased whereas interferon-gamma production was reduced. As a result, this microenvironment enhanced parasite proliferation. In contrast, PD-1 and PD-L1 blockage increased iNOS expression and NO production on peritoneal M phi s from T. cruzi-infected mice. Besides, PD-L2 knockout infected mice showed an increased in parasitaemia as well as in arginase activity, and a reduction in NO production. Taken together, our results demonstrate that PD-L2 is involved in the arginase/iNOS balance during T. cruzi infection having a protective role in the immune response against the parasite.