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

• Published in: Gut Vol. 67; no. 6; pp. 1155 - 1167
• Main Authors: Bernsmeier, Christine, Triantafyllou, Evangelos, Brenig, Robert, Lebosse, Fanny J, Singanayagam, Arjuna, Patel, Vishal C, Pop, Oltin T, Khamri, Wafa, Nathwani, Rooshi, Tidswell, Robert, Weston, Christopher J, Adams, David H, Thursz, Mark R, Wendon, Julia A, Antoniades, Charalambos Gustav
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group 01.06.2018; Gut
• Series: Original article
• Subjects: Acute-On-Chronic Liver Failure - immunology; Adult; Anti-Infective Agents - therapeutic use; Cytokines - metabolism; Flow Cytometry; Fucosyltransferases - metabolism; Hepatology; HLA-DR Antigens - metabolism; Humans; Immune Tolerance - immunology; Immunology; Immunophenotyping; Lewis X Antigen - metabolism; Life Sciences; Lipopolysaccharide Receptors - metabolism; Lymphocyte Activation - immunology; Middle Aged; Myeloid-Derived Suppressor Cells - immunology; Phagocytosis - immunology; Polymerase Chain Reaction; Prognosis; ACLF; MDSC; ALF; bacterial infection; immune suppression; cirrhosis
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2017-314184

ObjectiveImmune 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.DesignPatients 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.ResultsCirculating 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.ConclusionImmunosuppressive 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.