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CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction

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Title: CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction
Authors: Lebosse, F
Gudd, C
Tunc, E
Singanayagam, A
Nathwani, R
Triantafyllou, E
Pop, O
Kumar, N
Mukherjee, S
Zheng Hou, T
Quaglia, A
Zoulim, F
Wendon, J
Dhar, A
Thursz, M
Antoniades, C
Khamri, W
Item Type: Journal Article
Abstract: Background Cirrhosis-associated immune dysfunction (CAID) contributes to high sepsis risk in patients with chronic liver disease. Various innate and; to a lesser extent; adaptive immune dysfunctions have been described as contributors to CAID leading to immune-paresis and impaired anti-microbial response in cirrhosis. In this study, we examined the phenotype of CD8+ T cells in chronic liver disease with the aim to evaluate changes that might contribute to impaired immune responses. Methods Sixty patients with cirrhosis were prospectively recruited for this study. CD8+ T cells from peripheral blood, ascites and liver explants were characterized using flow cytometry and immunohistochemistry, respectively. The transcriptional signature of flow-sorted HLA-DR+CD8+ T cells was performed using Nanostring™ technology. HLA-DR+CD8+ T cells interactions with PBMCs and myeloid cells were tested in vitro. Findings Peripheral CD8+ T cells from cirrhotic patients displayed an altered phenotype characterized by high HLA-DR and TIM-3 surface expression associated with concomitant infections and disease severity, respectively. Paired peritoneal CD8+ T cells expressed more pronounced levels of HLA-DR and PD-1 compared to peripheral CD8+ T cells. HLA-DR+CD8+ T cells were enriched in cirrhotic livers compared to controls. TIM-3, CTLA-4 and PD-1 levels were highly expressed on HLA-DR+CD8+ T cells and co-expression of HLA-DR and PD1 was higher in patients with poor disease outcomes. Genes involved in cytokines production and intracellular signalling pathways were strongly down-regulated in HLA-DR+CD8+ T cells. In comparison to their HLA-DR− counterparts, HLA-DR+CD8+ T cells promoted less proliferation of PBMCs and induced phenotypic and functional dysfunctions in monocytes and neutrophils in vitro. Interpretation In patients with cirrhosis, CD8+ T cells display a phenotypic, functional and transcriptional profile which may contribute to CAID. Fund This work was supported by Medical Research Council, the Rosetrees Charitable Trust, Robert Tournut 2016 grant (Sociéte Nationale Française de GastroEntérologie), Gilead® sciences, and NIHR Imperial Biomedical Research Centre.
Issue Date: Nov-2019
Date of Acceptance: 8-Oct-2019
URI: http://hdl.handle.net/10044/1/74505
DOI: 10.1016/j.ebiom.2019.10.011
ISSN: 2352-3964
Publisher: Elsevier
Start Page: 258
End Page: 268
Journal / Book Title: EBioMedicine
Volume: 49
Copyright Statement: © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license. (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: BRC ITMAT Funding Scheme
Medical Research Council
Funder's Grant Number: MRC
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
Medicine, Research & Experimental
General & Internal Medicine
Research & Experimental Medicine
Cirrhosis-associated immune dysfunction
CD8(+) T cells
Chronic liver disease
CD8(+)T cells
Chronic liver disease
Cirrhosis-associated immune dysfunction
Publication Status: Published
Online Publication Date: 2019-10-31
Appears in Collections:Department of Metabolism, Digestion and Reproduction