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
Alimentary Pharmacology and Therapeutics
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 + 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-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.
Pal, Sourina; Nandi, Madhuparna; Dey, Debangana; Chakraborty, Bidhan Chandra; Shil, Achintya; Ghosh, Saurabh; Banerjee, Soma; Santra, Amal; Ahammed, S. K.Mahiuddin; Chowdhury, Abhijit; and Datta, Simanti, "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" (2019). Journal Articles. 855.