College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China.
Engineering Research Center of Prevention and Control of Cattle Diseases, Daqing, China.
Front Immunol. 2020 Mar 17;11:467. doi: 10.3389/fimmu.2020.00467. eCollection 2020.
Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocyte (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection . However, the immunomodulatory effects of PD-1 pathway on major PBL subsets are unclear and their underlying molecular mechanisms need to be further studied. Therefore, in this study, we examined PD-1 expression in bovine PBL subsets after BVDV infection and analyzed the effects of PD-1 blockade on the apoptosis and proliferation of CD4 and CD8 T cells and expression of PD-1 downstream signaling molecules. The results showed that PD-1 expression was enhanced on CD4 and CD8 T cells, but not on CD21 B cells after cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain KD) infection and PD-1 blockade significantly reduced the apoptosis of CD4 and CD8 T cells after these two strains infection. Remarkably, PD-1 blockade significantly increased the proliferation of CD4 and CD8 T cells after CP BVDV infection, but only significantly increased the proliferation of CD4 T cells after NCP BVDV infection. In addition, we confirmed that PD-1-mediated PI3K/Akt/mTOR, caspase 9/caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4 and CD8 T cells during BVDV infection . Notably, ERK is involved in the regulation mechanism PD-1 mediated only when the cells are infected with CP BVDV. Our findings provide a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.
牛病毒性腹泻病毒（BVDV）的急性感染与免疫功能障碍有关，并可导致外周血淋巴细胞减少和淋巴细胞凋亡。我们之前的研究已经证实，程序性死亡受体 1（PD-1）阻断可抑制外周血淋巴细胞（PBL）凋亡，并在 BVDV 感染后恢复淋巴细胞的增殖和抗病毒免疫功能。然而，PD-1 通路对主要 PBL 亚群的免疫调节作用尚不清楚，其潜在的分子机制需要进一步研究。因此，在本研究中，我们检测了 BVDV 感染后牛 PBL 亚群中 PD-1 的表达，并分析了 PD-1 阻断对 CD4 和 CD8 T 细胞凋亡和增殖以及 PD-1 下游信号分子表达的影响。结果表明，在细胞病变型（CP）BVDV（NADL 株）和非细胞病变型（NCP）BVDV（KD 株）感染后，CD4 和 CD8 T 细胞上的 PD-1 表达增强，但 CD21 B 细胞上无表达；PD-1 阻断显著降低了这两种毒株感染后 CD4 和 CD8 T 细胞的凋亡。值得注意的是，PD-1 阻断显著增加了 CP BVDV 感染后 CD4 和 CD8 T 细胞的增殖，但仅显著增加了 NCP BVDV 感染后 CD4 T 细胞的增殖。此外，我们证实 PD-1 介导的 PI3K/Akt/mTOR、caspase 9/caspase 3 和 ERK 通路参与调节 BVDV 感染过程中 CD4 和 CD8 T 细胞的凋亡和增殖。值得注意的是，ERK 仅参与 CP BVDV 感染时 PD-1 介导的调节机制。我们的研究结果为探索急性 BVDV 感染引起的免疫功能障碍的分子机制提供了科学依据。
