Dataset Information

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

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.

SUBMITTER: Lebosse F

PROVIDER: S-EPMC6945243 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

CD8<sup>+</sup>T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.

Lebossé Fanny F Gudd Cathrin C Tunc Enes E Singanayagam Arjuna A Nathwani Rooshi R Triantafyllou Evangelos E Pop Oltin O Kumar Naveenta N Mukherjee Sujit S Hou Tie Zheng TZ Quaglia Alberto A Zoulim Fabien F Wendon Julia J Dhar Ameet A Thursz Mark M Antoniades Charalambos G CG Khamri Wafa W

EBioMedicine 20191031

<h4>Background</h4>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<sup>+</sup>T cells in chronic liver disease with the aim to evaluate changes that might contribute to impaired immune respon ...[more]

PMID: 31678004

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Project description:Background & aimsCD161-expressing CD8+ T cells consist of mucosal-associated invariant T cells with semi-invariant T-cell receptor (TCR) use and non-mucosal-associated invariant T CD161+CD8+ T cells with polyclonal TCR repertoire. Although CD161+CD8+ T cells are enriched in liver and embrace hepatitis B virus (HBV)-specific T cells in chronic hepatitis B (CHB) patients, their roles in disease progression remain poorly understood. This study aimed to decipher their profiling and dynamic changes during chronic HBV infection.MethodsBlood samples from 257 CHB patients and nontumor liver specimens from 73 HBV-positive patients were analyzed for CD161+CD8+ T-cell characterization by flow cytometry, TCR repertoire determination, transcriptomic analyses, and cell experiments.ResultsCD161+CD8+ T cells were increased and hyperactivated in patients, while positive correlation between the CD161+CD8+ T-cell ratio and HBV-DNA level suggested this was insufficient to control HBV replication. The overlap of complementarity determining region 3 sequences supported the switch between CD161-CD8+ and CD161+CD8+ populations. Although CD161+CD8+ T cells were endowed with innateness phenotype and enhanced antiviral capacity, the population from patients had impaired type I cytokine production, and increased interleukin 17 and granzyme B secretion. The increased CD161+CD8+ T cells and their increased granzyme B secretion correlated positively with inflammation-associated liver injury. Hepatic CD161+CD8+ T cells showed neutrophil-related pathogenic potential because they had increased transcript signatures and proinflammatory cytokine production in neutrophil recruitment- and response-related pathways that changed consistently in the injured liver.ConclusionsOur results highlight the reduced antiviral potency but increased pathogenic potential of CD161+CD8+ T cells in CHB patients, supporting CD161 expression as a marker of pathogenic CD8+ T subset and the intervention target for liver injury.

Project description:Background & aimHepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis.MethodsWe isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8+ T-cell epitopes, and characterized HDV-specific CD8+ T cells. We associated these with HDV sequence variations and clinical features of patients.ResultsWe identified 6 CD8+ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8+ T cells correlated with transaminase activity. CD8+ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8+ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8+ T cells had a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation.ConclusionsCD8+ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8+ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226.

Project description:IntroductionThis study investigates the metabolic activity of circulating monocytes and their impact on pro-inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease.MethodsBlood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at-risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, Western blot, migration assays, Seahorse-XFe-technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue.ResultsCD14+ monocytes from RA patients are hyper-inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS-induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro-inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR.ConclusionRA CD14+ monocytes are metabolically re-programmed for sustained induction of pro-inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease.

Dataset Information

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

Background

Methods

Findings

Interpretation

Publications

CD8<sup>+</sup>T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Findings

Interpretation

Publications

CD8&lt;sup&gt;+&lt;/sup&gt;T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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

CD8<sup>+</sup>T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction.