Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Abstract

Although myeloid-derived suppressor cells (MDSCs) are well known for their immunosuppressive function in several pathological conditions, the role of MDSCs in hepatitis B virus infection remains obscure. In this study, we investigated the frequency and function of MDSCs in the peripheral blood and liver of 91 chronic hepatitis B (CHB) patients. A higher percentage of MDSCs, defined as CD14+HLA-DR−/low, was detected in peripheral blood of CHB patients than that of the healthy controls. Moreover, high expression of programmed death 1 (PD-1) and secretion of IL-10 in this population were determined. The frequency of MDSCs was positively correlated with serum viral load, but it was negatively correlated with liver inflammatory injury. These cells were also abundant in liver tissue of CHB patients and were related to necroinflammatory activity. Furthermore, we found that these cells could suppress hepatitis B virus–specific CD8+ T cell response, including reduced proliferation and IFN-γ production, and inhibit degranulation of CD8+ T cells, including reduced production of granzyme B and perforin. Importantly, PD-1–induced IL-10 production by MDSCs was responsible for the suppressive activity. To our knowledge, for the first time our study proved that CD14+HLA-DR–/lowPD-1+ MDSCs in CHB patients contribute to an inadequate immune response against the virus and lead to chronic infection, which represents a potential target for therapeutic intervention.

Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection

“…Our studies are not consistent with the observations of Huang et al (9), who found no correlation between HBsAg levels and MDSC numbers. However, their findings may have resulted from the definition of their population of MDSCs as CD14 + HLA-DR 2/low , whereas we defined mMDSCs by four markers as described.…”

“…These cells have been shown to suppress HBV-specific CD8 + T cell responses (9). However, the mechanisms involved in the expansion of MDSCs in patients with CHB have not been identified.…”

“…The expansion of MDSCs in HBV patients and mouse models has been reported (8,9 (16,17). Thus, spleen and liver leukocytes were isolated and first gated by CD11b, then Gr-1 and Ly6c were used to define the MDSC population.…”

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…Studies have shown that liver is one of the major sites of MDSCs, in addition to the immune organs (28). Accumulation of MDSC in liver has been observed in tumor-bearing hosts, hepatitis B virus-infected individuals, and high fat dietfed animals (4,29,30). Also, hepatic stellate cells were reported to support the expansion of MDSCs in vitro (31).…”

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

“…One striking finding of this study is that there are significant correlations between the levels of antigenstimulated cIL-10 production in PBMC and RhCMV genome copy numbers detected in saliva. This is not unique to RhCMV, as cIL-10 levels have been positively associated, either alone or with other biomarkers, with increased burdens of other pathogens, including human papillomavirus, HIV, hepatitis B virus, EpsteinBarr virus (EBV), Mycobacterium tuberculosis, Leishmania spp., dengue virus, and murine and human CMV (45,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72). While the specific cell type(s) responsible for elevated cIL-10 expression in response to RhCMV antigen exposure was not explored, multiple cell types have been implicated for other pathogens, including regulatory B and T cells.…”