Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia; University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia.
Int Immunopharmacol. 2021 Oct;99:107978. doi: 10.1016/j.intimp.2021.107978. Epub 2021 Jul 20.
Interferon-γ (IFN-γ) is the sole representative of type II IFNs, with well recognized role in numerous inflammatory processes. Lately, its significant pleiotropic nature has been recognized in many scenarios, where IFN-γ contributes to maintenance or induction of tolerogenic responses in context of various immune cell types. In this manuscript we demonstrate, that IFN-γ-mediated induction of programmed death ligand 1 (PD-L1) on human monocyte-derived dendritic cells (DCs) represents an important tolerogenic aspect in immunological network of type II IFNs. When fully differentiated, immature DCs were treated with increasing concentrations of IFN-γ there was no sign of maturation, as revealed by CD80, CD83 and CD86 expression. In terms of co-stimulatory receptor response, we did observe a dose-dependent increase in CD40 expression. Phenotypic analysis of inhibitory molecules revealed that PD-L1 expression is particularly sensitive to IFN-γ, as its expression can be induced almost 10-fold in comparison to non-treated DCs. Functional analysis of such PD-L1 DCs revealed significant immunosuppressive properties in a mixed lymphocyte reaction with whole or memory CD4 T cells. When IFN-γ treated DCs were co-cultured with naive CD4CD45RA T cells, they induced an increased percentage of CD4CD25CD127FoxP3 Tregs. Inhibition of PD-1/PD-L1 axis using neutralizing anti-PD-L1 mAbs, reversed the immunosuppressive effect of IFN-γ-treated DCs to suppress CD4 T cell proliferation and to induce Tregs. In summary, our findings demonstrate the importance of IFN-γ-mediated tolerogenic effects, exerted on DCs by inducing increased expression of PD-L1, which enhances their regulatory function.
干扰素-γ (IFN-γ) 是 II 型 IFNs 的唯一代表，在众多炎症过程中具有公认的作用。最近，在许多情况下，其显著的多效性已被认识到，IFN-γ 在各种免疫细胞类型中有助于维持或诱导耐受反应。在本文中，我们证明了 IFN-γ 在人单核细胞来源的树突状细胞 (DC) 上诱导程序性死亡配体 1 (PD-L1) 的表达代表了 II 型 IFNs 免疫网络中一个重要的耐受方面。当完全分化时，用递增浓度的 IFN-γ 处理未成熟的 DC，不会有成熟的迹象，如 CD80、CD83 和 CD86 的表达。就共刺激受体反应而言，我们确实观察到 CD40 表达的剂量依赖性增加。抑制性分子的表型分析表明，PD-L1 的表达对 IFN-γ 特别敏感，因为与未经处理的 DC 相比，其表达可诱导近 10 倍。这种 PD-L1 DC 的功能分析显示，在与全或记忆 CD4 T 细胞的混合淋巴细胞反应中具有显著的免疫抑制特性。当用 IFN-γ 处理的 DC 与幼稚的 CD4CD45RA T 细胞共培养时，它们诱导 CD4CD25CD127FoxP3 Treg 的百分比增加。使用中和抗 PD-L1 mAb 抑制 PD-1/PD-L1 轴，可逆转 IFN-γ 处理的 DC 的免疫抑制作用，抑制 CD4 T 细胞增殖并诱导 Treg。总之，我们的发现表明了 IFN-γ 介导的耐受效应的重要性，通过诱导 PD-L1 的表达增加，增强了 DC 的调节功能。
