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

BackgroundCD4(+) 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. AimTo 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. MethodsMultiparametric flow cytometry, cell-sorting and co-culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir. ResultsHLA-DR(-)CD11b(+)CD33(hi)-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(+)CD33(low)-granulocytic-MDSC from IT and EP-/EN-CHB expressed high transforming growth factor beta (TGF-) 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- 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. ConclusionsWe established a previously unrecognised role of MDSC in Treg development in IT and EP-/EN-CHB via TGF-/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.