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

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

doi:10.1016/j.ebiom.2019.10.011

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

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^*

^*Corresponding author for this work

Inflammation Biology

Research output: Contribution to journal › Article › peer-review

64 Citations (Scopus)

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.

Original language	English
Pages (from-to)	258-268
Number of pages	11
Journal	EBioMedicine
Volume	49
DOIs	https://doi.org/10.1016/j.ebiom.2019.10.011
Publication status	Published - 1 Nov 2019

Keywords

CD8 T cells
Chronic liver disease
Cirrhosis-associated immune dysfunction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ebiom.2019.10.011

Cite this

Lebossé, F., Gudd, C., Tunc, E., Singanayagam, A., Nathwani, R., Triantafyllou, E., Pop, O., Kumar, N., Mukherjee, S., Hou, T. Z., Quaglia, A., Zoulim, F., Wendon, J., Dhar, A., Thursz, M., Antoniades, C. G., & Khamri, W. (2019). CD8⁺ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction. EBioMedicine, 49, 258-268. https://doi.org/10.1016/j.ebiom.2019.10.011

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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{\texttrademark} 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 (Soci{\'e}te Nationale Fran{\c c}aise de GastroEnt{\'e}rologie), Gilead{\textregistered} sciences, and NIHR Imperial Biomedical Research Centre.",

keywords = "CD8 T cells, Chronic liver disease, Cirrhosis-associated immune dysfunction",

author = "Fanny Leboss{\'e} and Cathrin Gudd and Enes Tunc and Arjuna Singanayagam and Rooshi Nathwani and Evangelos Triantafyllou and Oltin Pop and Naveenta Kumar and Sujit Mukherjee and Hou, {Tie Zheng} and Alberto Quaglia and Fabien Zoulim and Julia Wendon and Ameet Dhar and Mark Thursz and Antoniades, {Charalambos G.} and Wafa Khamri",

year = "2019",

month = nov,

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doi = "10.1016/j.ebiom.2019.10.011",

language = "English",

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pages = "258--268",

journal = "EBioMedicine",

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publisher = "Elsevier BV",

}

Lebossé, F, Gudd, C, Tunc, E, Singanayagam, A, Nathwani, R, Triantafyllou, E, Pop, O, Kumar, N, Mukherjee, S, Hou, TZ, Quaglia, A, Zoulim, F, Wendon, J, Dhar, A, Thursz, M, Antoniades, CG & Khamri, W 2019, 'CD8⁺ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction', EBioMedicine, vol. 49, pp. 258-268. https://doi.org/10.1016/j.ebiom.2019.10.011

TY - JOUR

T1 - CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction

AU - Lebossé, Fanny

AU - Gudd, Cathrin

AU - Tunc, Enes

AU - Singanayagam, Arjuna

AU - Nathwani, Rooshi

AU - Triantafyllou, Evangelos

AU - Pop, Oltin

AU - Kumar, Naveenta

AU - Mukherjee, Sujit

AU - Hou, Tie Zheng

AU - Quaglia, Alberto

AU - Zoulim, Fabien

AU - Wendon, Julia

AU - Dhar, Ameet

AU - Thursz, Mark

AU - Antoniades, Charalambos G.

AU - Khamri, Wafa

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

KW - CD8 T cells

KW - Chronic liver disease

KW - Cirrhosis-associated immune dysfunction

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