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

Research output: Contribution to journalArticle

Fanny Lebossé, Cathrin Gudd, Enes Tunc, Arjuna Singanayagam, Rooshi Nathwani, Evangelos Triantafyllou, Oltin Pop, Naveenta Kumar, Sujit Mukherjee, Tie Zheng Hou, Alberto Quaglia, Fabien Zoulim, Julia Wendon, Ameet Dhar, Mark Thursz, Charalambos G. Antoniades, Wafa Khamri

Original languageEnglish
Pages (from-to)258-268
Number of pages11
JournalEBioMedicine
Volume49
DOIs
Publication statusPublished - 1 Nov 2019

King's Authors

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.

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