Suppressor CD4⁺T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis

Abstract

ObjectiveIdentifying 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).DesignFlow cytometry was used to determine the proportion and immunophenotype of CD4+HLA-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 CD4+HLA-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.ResultsPatients with AD were distinguished by an expansion of a CD4+HLA-G+CTLA-4+IL-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.ConclusionWe have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.

Risk factors for the development of sepsis in patients with cirrhosis in intensive care units

“…For the first time, this study provided a relatively accurate tool to predict the risk of sepsis among patients with liver cirrhosis, which demonstrated good discrimination and calibration power. There were three noteworthy features in our study: (1) a large number of patients were included in the study; (2) the variables used in the model can easily be obtained in the clinical setting; and (3) the nomogram demonstrated greater predictive performance in both training and validation cohorts. Many experimental and clinical studies have demonstrated that sepsis and infectious diseases differ according to gender.…”

“…Liver cirrhosis is a leading cause of death and morbidity worldwide in a wide range of chronic liver diseases, 1 characterized by diffuse fibrosis, disruption of intrahepatic venous flow, and portal hypertension, which may result in liver failure. 2 There are nearly two million deaths caused by liver cirrhosis each year, making liver cirrhosis one of the top 10 leading causes of death in the world. 3 , 4 Liver cirrhosis accounts for ~2% to 4% of all deaths worldwide.…”