Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.
Gut. 2022 Jun;71(6):1192-1202. doi: 10.1136/gutjnl-2021-324071. Epub 2021 Aug 3.
Identifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4 T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4 T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD).
Flow cytometry was used to determine the proportion and immunophenotype of CD4HLA-G T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4HLA-G cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.
Patients with AD were distinguished by an expansion of a CD4HLA-GCTLA-4IL-35 immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.
We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.
识别免疫抑制的组成部分，这是慢性肝功能衰竭的一个标志，对于我们理解肝硬化的并发症至关重要。各种抑制性 CD4 T 细胞已被确定为全身免疫激活的有效抑制剂。在这里，我们在急性肝硬化失代偿（AD）患者中建立了表达人类白细胞抗原 G（HLA-G）的抑制性 CD4 T 细胞亚群的存在、调节和作用机制。
流式细胞术用于确定来自 20 名健康对照（HC）和 98 名肝硬化患者（28 名稳定肝硬化（SC），20 名慢性失代偿性肝硬化（CD）和 50 名 AD）外周血中 CD4HLA-G T 细胞的比例和免疫表型。通过 NanoString 技术和抑制试验分别描绘细胞分选 CD4HLA-G 细胞的转录和功能特征。通过体外阻断实验研究免疫抑制细胞因子白细胞介素（IL）-35 在诱导该群体中的作用。进行免疫组织化学（IHC）和原代人库普弗细胞（KCs）培养以评估 IL-35 的细胞来源。使用针对共抑制途径的中和抗体探索 HLA-G 介导的 T 细胞抑制。
AD 患者的特征是 CD4HLA-GCTLA-4IL-35 免疫抑制群体的扩张与疾病严重程度、AD 的临床过程、感染并发症和不良预后相关。转录组分析排除了这些是胸腺来源的调节性 T 细胞的可能性。IHC 分析和体外培养表明 KCs 是 IL-35 的一个强有力来源，可诱导观察到的 HLA-G 表型。这些在 T 细胞中表现出细胞毒性 T 淋巴细胞抗原-4 介导的受损反应，同时 HLA-G 驱动 Th17 相关细胞因子的下调。
我们已经确定了一种由细胞因子驱动的外周衍生抑制性群体，它可能导致 AD 中的免疫抑制。
