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.

Keywords: CD8(+)T cells; Chronic liver disease; Cirrhosis-associated immune dysfunction.