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

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Title: Suppressor CD4+ T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis
Authors: Khamri, W
Gudd, C
Liu, T
Nathwani, R
Krasniqi, M
Azam, S
Barbera, T
Trovato, FM
Possamai, LA
Triantafyllou, E
Castro Seoane, R
Lebosse, F
Singanayagam, A
Kumar, N
Bernsmeier, C
Mukherjee, S
McPhail, MJW
Weston, CJ
Antoniades, CG
Thursz, MR
Item Type: Journal Article
Abstract: Objective 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). Design Flow 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. Results Patients 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. Conclusion We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.
Issue Date: 3-Aug-2021
Date of Acceptance: 22-Jul-2021
URI: http://hdl.handle.net/10044/1/90704
DOI: 10.1136/gutjnl-2021-324071
ISSN: 0017-5749
Publisher: BMJ Publishing Group
Start Page: 1192
End Page: 1202
Journal / Book Title: Gut
Volume: 71
Issue: 6
Copyright Statement: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: BRC ITMAT Funding Scheme
Medical Research Council
Medical Research Council
Funder's Grant Number: MRC
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
immunology in hepatology
immunoregulation
ANTIGEN-PRESENTING CELLS
CHRONIC LIVER-FAILURE
IMMUNE CELLS
PROLIFERATION
INDUCTION
EXPANSION
CYTOKINE
SUBSET
SYSTEM
IL-35
immunology in hepatology
immunoregulation
CD4-Positive T-Lymphocytes
Cytokines
HLA-G Antigens
Humans
Interleukins
Liver Cirrhosis
T-Lymphocyte Subsets
T-Lymphocyte Subsets
CD4-Positive T-Lymphocytes
Humans
Liver Cirrhosis
Interleukins
Cytokines
HLA-G Antigens
Gastroenterology & Hepatology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Publication Status: Published
Online Publication Date: 2021-08-03
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons