A subset of liver resident natural killer cells is expanded in hepatitis C-infected patients with better liver function

Erin H Doyle,Arielle L Klepper,Sander S Florman,Ahmed El-Shamy,Adeeb Rahman,Costica Aloman,Thomas Schiano,Andrea D Branch,Francis Eng,Brandy Haydel,M Isabel Fiel

doi:10.1038/s41598-020-80819-8

Abstract

Viral hepatitis leads to immune-mediated liver injury. The rate of disease progression varies between individuals. We aimed to phenotype immune cells associated with preservation of normal liver function during hepatitis C virus (HCV) infection. Clinical data and specimens were obtained from 19 HCV-infected patients undergoing liver transplantation. Liver and peripheral blood mononuclear cells were isolated and eight subsets of innate immune cells were delineated by multiparameter flow cytometry. Cytokine assays and microarrays were performed. Intrahepatic CD56Bright/CD16- natural killer (NK) cells comprised the only subset correlating with better liver function, i.e., lower bilirubin (p = 0.0002) and lower model for end stage of liver disease scores (p = 0.03). The signature of liver NK cells from HCV-infected patients included genes expressed by NK cells in normal liver and by decidual NK cells. Portal vein blood had a higher concentration of interleukin (IL)-10 than peripheral blood (p = 0.03). LMCs were less responsive to toll-like receptor (TLR) stimulation than PBMCs, with fewer pro-inflammatory gene-expression pathways up-regulated after in vitro exposure to lipopolysaccharide and a TLR-7/8 agonist. Hepatic CD56Bright/CD16- NK cells may be critical for maintaining liver homeostasis. Portal vein IL-10 may prime inhibitory pathways, attenuating TLR signaling and reducing responsiveness to pro-inflammatory stimuli.

Highlights

Abbreviations ALT Alanine aminotransferase CD Cluster differentiation GGT Gamma-glutamyl transferase hepatitis B virus (HBV) Hepatitis B virus hepatitis C virus (HCV) Hepatitis C virus IFN Interferon IL Interleukin INR International normalized ratio IQR Interquartile range Liver mononuclear cells (LMCs) Liver mononuclear cell LPS Lipopolysaccharide Model for end stage liver disease (MELD) Model of end-stage liver disease natural killer (NK) Natural killer PAMPS Pathogen associated molecular patterns peripheral blood mononuclear cells (PBMCs) Peripheral blood mononuclear cell toll-like receptor (TLR) Toll-like receptor TNFα Tumor necrosis factor alpha
This study revealed a strong association between the abundance of human liver C D56Bright/CD16- NK cells and measures liver function, such as lower total bilirubin concentration in serum, lower MELD scores, and expression of molecular pathways associated with normal liver functions
In contrast to the NK cells, the abundance of hepatic monocytes/macrophages was associated with increased liver injury and dysfunction, consistent with published data implicating these cells in liver damage

Summary

Introduction

Abbreviations ALT Alanine aminotransferase CD Cluster differentiation GGT Gamma-glutamyl transferase HBV Hepatitis B virus HCV Hepatitis C virus IFN Interferon IL Interleukin INR International normalized ratio IQR Interquartile range LMC Liver mononuclear cell LPS Lipopolysaccharide MELD Model of end-stage liver disease NK Natural killer PAMPS Pathogen associated molecular patterns PBMC Peripheral blood mononuclear cell TLR Toll-like receptor TNFα Tumor necrosis factor alpha. It is a priority to increase knowledge of the hepatic cells, including the immune cell subsets, that preserve and restore liver function. Liver damage is often immune-mediated[7]; immunosuppression can accelerate pathogenesis, as seen in HCV-infected patients with inborn immunodeficiencies[8], HIV infection[9], or on immunosuppressive d rugs[10], implying that, in the absence of immunosuppression, cytotoxic immune cells are held in check by other immune cell subsets. A promising strategy for improving outcomes in liver disease patients is to identify the immune cell subsets that modulate immunopathology, promote repair, and maintain homeostasis. We analyzed innate immune cell populations in liver and peripheral blood of 19 HCV-infected adults undergoing liver transplantation, seeking subsets expanded in patients with relatively well-preserved liver function. If liver CD56Bright/CD16- NK cells act through similar mechanisms, greater knowledge of their secretome and cell to cell interactions could lead to interventions that increase their activity and thereby improve liver function

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Conclusion