Myeloid‐derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy

Abstract

Summary Background CD4+ regulatory T‐cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity, although the underlying mechanism remains largely elusive. Myeloid‐derived suppressor cells (MDSC) have been linked with T‐cell dysfunction but questions remain regarding their persistence/profile/function in chronically HBV infected patients. Aim To characterise MDSC in different phases of chronic HBV infection namely, immune‐tolerant (IT), hepatitis B e‐antigen‐positive chronic hepatitis B (EP‐CHB), inactive carriers (IC) and hepatitis B e‐antigen‐negative chronic hepatitis B (EN‐CHB), to investigate their role in Treg induction and evaluate the effect of anti‐viral therapy on these cells. Methods Multiparametric flow cytometry, cell‐sorting and co‐culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir. Results HLA‐DR‐CD11b+CD33hi‐Monocytic‐MDSC (M‐MDSC) were enhanced in IT, EP‐CHB and EN‐CHB compared with IC, and this was related to increasing hepatitis B surface antigen (HBsAg) concentration. IT and EP‐/EN‐CHB displayed elevated frequency of CD4+CD25+FOXP3+Treg that positively correlated with that of M‐MDSC. However, both M‐MDSC and HLA‐DR‐CD11b+CD33low‐granulocytic‐MDSC from IT and EP‐/EN‐CHB expressed high transforming growth factor beta (TGF‐β) and interleukin‐10 (IL‐10). Co‐culture of sorted HLA‐DR‐CD33+‐MDSC with autologous MDSC depleted‐PBMC from IT and CHB but not from IC, increased CD4+CD25+FOXP3+‐iTreg and CD4+FOXP3‐IL‐10+‐Tr1‐cells through a cell‐contact independent mechanism. While MDSC‐derived TGF‐β and IL‐10 promoted development of iTreg, only IL‐10 appeared to be crucial for Tr1 induction. One year of tenofovir treatment failed to normalise MDSC frequency/function or reduce Treg percentage and serum HBsAg levels, despite reduction in viral load. Conclusions We established a previously unrecognised role of MDSC in Treg development in IT and EP‐/EN‐CHB via TGF‐β/IL‐10‐dependent pathways and both cell‐types persisted after anti‐viral therapy. Hence, therapeutic targeting of MDSC or reducing circulating HBsAg level together with tenofovir‐therapy might be more effective in restricting HBV persistence and disease progression.

Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma

“…The results revealed that MDSCs did not associate with any parameters of tumor burden and overall survival but positively correlated with several markers for hepatic injury. Evidence of our current study and previous data have shown the involvement of MDSCs in the pathogenesis of chronic HBV infection [19,20]. Taken together, compared to the role of promoting HCC progression, MDSCs seem to play a more important role in the process leading from infection to cancer.…”

Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

“…These data partially challenge previously published data that reported robust MDSC expansion in infections and non-malignant inflammatory diseases such as psoriasis, HIV, HBV and CVDs. [23][24][25][26][27]…”

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

“…A recent study in chronically HBV infected patients with high levels of HBsAg revealed the capacity of MDSCs to promote immune dysfunction through the induction of regulatory T cells, primarily via TGF-β and IL-10 dependent signaling pathways. Interestingly, a year tenofovir treatment did not result in the immune restoration of the regulatory MDSC and Treg populations (152). In addition, circulating MDSCs were significantly expanded in patients with HBV-related acute-onchronic liver failure (ACLF) and closely associated with disease progression and severity.…”