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

Abstract

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.

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

“…We recently identified that monocytes from ALF and ACLF patients, and to a lesser extent from patients with cirrhosis without organ failure, exhibit an immune regulatory HLA-DR High MER-TK + phenotype [11,12] . Additionally, we reported an expansion of myeloid-derived suppressors CD14 + CD15 − HLA-DR − cells in patients with ACLF [13] .…”

“…In patients presenting alcohol-related liver diseases (ALD), profound impaired oxidative burst and bactericidal functions of polymorphonuclear neutrophils (PMNs) and monocytes were observed [6][7][8][9][10] . In patients with acute liver failure (ALF) and ACLF, pro-inflammatory conditions could drive an in vivo anti-inflammatory monocyte phenotype which was associated with a defective anti-bacterial response in vitro [11][12][13] . We recently identified that monocytes from ALF and ACLF patients, and to a lesser extent from patients with cirrhosis without organ failure, exhibit an immune regulatory HLA-DR High MER-TK + phenotype [11,12] .…”

Infections complicating cirrhosis

“…Finally, in patients with severe cirrhosis, namely those with ACLF, monocytes show an overexpression of MERTK receptors that mediates a blunted inflammatory response to lipopolysaccharide (LPS) stimulation . Mononuclear myeloid‐derived suppressor cells are increased, which decreases T‐cell proliferation, produces less TNF‐alpha following TLR stimulation, and reduces bacterial uptake of E. coli . Interestingly, it has been shown that patients with ACLF have a very high short‐term occurrence of bacterial and fungal infections, which may be related to this condition of “immune paralysis” …”

“…18 Mononuclear myeloid-derived suppressor cells are increased, which decreases T-cell proliferation, produces less TNF-alpha following TLR stimulation, and reduces bacterial uptake of E. coli. 19 Interestingly, it has been shown that patients with ACLF have a very high short-term occurrence of bacterial and fungal infections, which may be related to this condition of "immune paralysis". 4 Among the immune cells that are involved in acquired immunity, (Figure 1).…”

Management of Infectious Complications Associated with Acute-on-Chronic Liver Failure

“…Patients who survived either an ACLF-related infection or prolonged intensive care unit stay migrate into an immunosuppressive state [24,30]. Monocytes and other phagocyting cells are less active with a reduced expression of human leukocyte antigen-antigen D related (HLA-DR), and as a consequence show an impaired response to LPS stimulation [31]. This hampers the clearance of invading bacteria, ultimately increasing the risk for secondary infectious complications [32].…”