Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan.
Front Immunol. 2021 Nov 25;12:767666. doi: 10.3389/fimmu.2021.767666. eCollection 2021.
Bronchial epithelial cells are front sentinels eliciting innate and adaptive immunity to respiratory viral pathogens. Recognition of viral double-stranded RNA induces antiviral interferon (IFN) responses in bronchial epithelial cells. Co-inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) were also induced on bronchial epithelial cells, which bind programmed cell death 1 on T cell and inhibit the function of virus-specific cytotoxic T lymphocyte. A previous study showed that antiviral type I IFN increased PD-L1 and PD-L2 expression in cultured melanoma cells. However, it remains unknown whether antiviral IFNs affect PD-L1 and PD-L2 expression in bronchial epithelial cells. In addition, we previously reported that inhibition of PI3Kδ signaling enhanced antiviral IFN responses in human primary bronchial epithelial cells (PBECs). Here we assessed the effect of exogenous IFNs or a selective PI3Kδ inhibitor IC87114 on PD-L1 and PD-L2 in PBECs stimulated with a synthetic double-stranded RNA poly I:C or human metapneumovirus. Treatment with IFNβ or IFNλ increased PD-L1 and PD-L2, and IFNβ or IFNλ treatment plus poly I:C further increased both expressions. Treatment with IC87114 or transfection with siRNA targeting PI3K p110δ enhanced poly I:C-induced gene and protein expression of PD-L2, whereas IC87114 suppressed poly I:C-induced PD-L1. IC87114 enhanced poly I:C-induced gene expression of IFNβ, IFNλ, and IFN-regulated genes increased TBK1 and IRF3 phosphorylation. Transfection with siIRF3 counteracted the enhancement of poly I:C-induced PD-L2 by IC87114, whereas IC87114 suppressed poly I:C-induced PD-L1 regardless of transfection with siNC or siIRF3. Similar effects of IC87114 on PD-L1 and PD-L2 expression were observed in human metapneumovirus-infected PBECs. We showed for the first time that type I and type III IFNs induced the expression of PD-L1 and PD-L2 in PBECs. Our findings suggest that during viral infections, inhibition of PI3Kδ differentially regulates PD-L1 and PD-L2 expression in bronchial epithelial cells.
气道上皮细胞是引发针对呼吸道病毒病原体的固有和适应性免疫的前沿哨兵。病毒双链 RNA 的识别会诱导气道上皮细胞产生抗病毒干扰素 (IFN) 反应。同时，气道上皮细胞也会诱导表达共抑制分子程序性细胞死亡蛋白 1 配体 1（PD-L1）和配体 2（PD-L2），它们与 T 细胞上的程序性细胞死亡蛋白 1 结合并抑制病毒特异性细胞毒性 T 淋巴细胞的功能。先前的研究表明，抗病毒 I 型 IFN 会增加培养的黑色素瘤细胞中 PD-L1 和 PD-L2 的表达。然而，目前尚不清楚抗病毒 IFNs 是否会影响气道上皮细胞中 PD-L1 和 PD-L2 的表达。此外，我们之前曾报道，抑制 PI3Kδ 信号可增强人原代气道上皮细胞 (PBEC) 中的抗病毒 IFN 反应。在这里，我们评估了外源性 IFN 或选择性 PI3Kδ 抑制剂 IC87114 对 Poly I:C 或人偏肺病毒刺激的 PBEC 中 PD-L1 和 PD-L2 的影响。IFNβ 或 IFNλ 的处理增加了 PD-L1 和 PD-L2 的表达，IFNβ 或 IFNλ 的处理加 Poly I:C 进一步增加了这两种表达。PI3K p110δ 的 IC87114 处理或靶向 siRNA 转染增强了 Poly I:C 诱导的 PD-L2 基因和蛋白表达，而 IC87114 抑制了 Poly I:C 诱导的 PD-L1。IC87114 增强了 Poly I:C 诱导的 IFNβ、IFNλ 和 IFN 调节基因的基因表达，增加了 TBK1 和 IRF3 的磷酸化。siIRF3 的转染抵消了 IC87114 对 Poly I:C 诱导的 PD-L2 的增强作用，而 IC87114 抑制了 Poly I:C 诱导的 PD-L1，无论转染 siNC 还是 siIRF3。在人偏肺病毒感染的 PBEC 中也观察到了类似的 IC87114 对 PD-L1 和 PD-L2 表达的影响。我们首次表明，I 型和 III 型 IFN 诱导 PBEC 中 PD-L1 和 PD-L2 的表达。我们的研究结果表明，在病毒感染期间，PI3Kδ 的抑制以不同的方式调节气道上皮细胞中 PD-L1 和 PD-L2 的表达。
