Myeloid-derived suppressor cells in non-malignant and non-infectious liver disease

BackgroundMyeloid-derived suppressor cells (MDSC) have been described as potent immunosuppressive cells in malignant and infectious liver disease. However, little is known about their role in non-infectious or non-malignant disease. We sought to characterise MDSC in patients with chronic non-infectious or non-malignant liver disease.MethodsExplants obtained from 12 patients undergoing liver transplantation and blood from 30 patients treated for haemochromatosis at the Queen Elizabeth Hospital, Birmingham, were analysed for the frequency of functional CD14+ HLA-DR– monocytic MDSC. Functional capacity was defined as the capability to suppress proliferation of maximally stimulated, CFSE-labelled CD4 T cells using CD3/CD28-beads (Dynabeads, LifeTechnologies, UK) at a ratio of 1:1. Additionally, MDSC were analysed for their capacity to induce CD4 regulatory T cells (assessed by FoxP3 expression) in cells activated with CD2/CD3/CD28-beads (Miltenyi, Germany). Both MDSC and CD4 cells were isolated by magnet-activated cell-sorting using a combination of depletion steps and positive-selection-steps. Analysis of frequency and immunotyping of MDSC was performed with flow-cytometry.FindingsCD14+ HLA-DR– MDSC obtained both from liver tissue and peripheral blood were able to suppress proliferation of CD4 T cells and to induce FOXP3-expression in CD4 T cells, typical of regulatory T cells. No such findings were observed when using CD14+ HLA-DR+ monocytes. Moreover, MDSC depleted of CD16+ monocytes showed weaker immunosuppressive capacity. In patients with haemochromatosis, the frequency of CD14+ HLA-DR– MDSC in peripheral blood ranged from 0·5% to 79% and in the liver of cirrhotic patients from 9·1% to 75·5%.InterpretationCD14+ HLA-DR– MDSC are fully functional in patients who have non-infectious or non-malignant liver disease. Similar to HLA-DR+ monocytes, CD16 expression may identify subtypes of monocytic MDSC with distinct immunoregulatory properties. Given the varying frequency of MDSC in the patients analysed, the clinical relevance of MDSC in non-malignant and non-infectious liver-disease has to be further analysed since they may influence the course of disease in these patients.FundingDeutsche Forschungsgemeinschaft and Liver Foundation Trust Fund.