CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

Abstract

OBJECTIVE:

Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.

DESIGN:

Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.

RESULTS:

Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.

CONCLUSION:

Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.

• Authors: Christine Bernsmeier, Evangelos Triantafyllou, Robert Brenig, Fanny J Lebosse, Arjuna Singanayagam, Vishal C Patel, Oltin T Pop, Wafa Khamri, Rooshi Nathwani, Robert Tidswell, Christopher J Weston, David H Adams, Mark R Thursz, Julia A Wendon, Charalambos Gustav Antoniades
• Journal: Gut (Gut) Vol. 67 Issue 6 Pg. 1155-1167 (06 2018) ISSN: 1468-3288 [Electronic] England
• PMID: 28592438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Anti-Infective Agents
• Cytokines
• HLA-DR Antigens
• Lewis X Antigen
• Lipopolysaccharide Receptors
• FUT4 protein, human
• Fucosyltransferases

Topics

• Acute-On-Chronic Liver Failure (immunology)
• Adult
• Anti-Infective Agents (therapeutic use)
• Cytokines (metabolism)
• Flow Cytometry
• Fucosyltransferases (metabolism)
• HLA-DR Antigens (metabolism)
• Humans
• Immune Tolerance (immunology)
• Immunophenotyping
• Lewis X Antigen (metabolism)
• Lipopolysaccharide Receptors (metabolism)
• Lymphocyte Activation (immunology)
• Middle Aged
• Myeloid-Derived Suppressor Cells (immunology)
• Phagocytosis (immunology)
• Polymerase Chain Reaction
• Prognosis