Programmed death ligand 1 (PD-L1) up-regulation on antigen presenting cells induces T cell dysfunction, strongly impairing immune response.

Human Herpesviruses (HHV) 6B is a β-herpesvirus that, although displays a higher tropism for T cells, can infect other immune cells including monocytes and dendritic cells (DCs) and neuronal cells. We have previously shown that HHV-6B infection of primary monocytes reduced autophagy and induced Endoplasmic Reticulum (ER) stress/ Unfolded Protein Response (UPR), impairing their survival and differentiation into DCs. In this study, we found that PD-L1 expression was up-regulated by HHV-6B on the surface of infected monocytes and that its extracellular release also increased, effects known to lead to an impairment of anti-viral immune response. At molecular level, PD-L1 up-regulation correlated with the activation of a positive regulatory circuit between the increase of intracellular ROS and the activation of STAT1 and STAT3 induced by HHV-6B, accompanied by a high release of pro-inflammatory/immune suppressive cytokines. In conclusion, this study unveils new strategies put in place by HHV-6B to induce immune dysfunction and the underlying molecular pathways that could be targeted to counteract such immune suppressive effects.

抗原呈递细胞上的程序性死亡配体 1 (PD-L1) 上调诱导 T 细胞功能障碍，严重损害免疫反应。

人类疱疹病毒 (HHV) 6B 是一种 β-疱疹病毒，虽然对 T 细胞显示出更高的趋向性，但可以感染其他免疫细胞，包括单核细胞和树突细胞 (DC) 以及神经元细胞。我们之前已经表明，原代单核细胞的 HHV-6B 感染减少了自噬并诱导了内质网 (ER) 应激/未折叠蛋白反应 (UPR)，损害了它们的存活和向 DC 的分化。在这项研究中，我们发现受感染单核细胞表面的 HHV-6B 上调了 PD-L1 表达，并且其细胞外释放也增加，已知的影响会导致抗病毒免疫反应受损。在分子水平上，PD-L1 上调与细胞内 ROS 增加与 HHV-6B 诱导的 STAT1 和 STAT3 激活之间的正调节回路的激活相关，伴随着促炎/免疫抑制细胞因子的大量释放。总之，这项研究揭示了 HHV-6B 为诱导免疫功能障碍而采取的新策略，以及可以针对抵消这种免疫抑制作用的潜在分子途径。