Diverse facets of MDSC in different phases of chronic HBV infection: Impact on HBV‐specific T‐cell response and homing

Abstract

Background and Aims Chronic HBV infection (CHI) is associated with a diverse natural history that includes immune‐tolerant (IT), HBeAg‐positive chronic hepatitis B (CHB) (EP‐CHB), inactive carrier, and HBeAg‐negative CHB (EN‐CHB) phases. A hallmark of CHI is impairment of HBV‐specific T‐cell response. Recently, myeloid‐derived suppressor cells (MDSCs) have emerged as key regulator of T cells, and their properties are sculpted by their microenvironment. Here, we investigated the distinctive features of MDSCs during CHI, identified factors responsible for their functional discrepancies, and studied their impact on HBV‐specific T‐cell response and homing. Influence of antiviral therapy on MDSC profile and T‐cell response was also assessed. Approach and Results Flow cytometric analysis indicated that MDSCs in EP‐CHB/EN‐CHB patients had profound suppressive ability, expressing arginase 1 (Arg1)/inducible nitric oxide synthase (iNOS)/programmed death ligand 1 (PD‐L1)/cytotoxic T lymphocyte–associated protein 4 (CTLA‐4)/CD40 at significantly greater levels relative to healthy controls (HC). However, in IT, only Arg1+ MDSCs and in inactive carrier, iNOS+ and PD‐L1+ MDSCs were higher than HC. In vitro assays demonstrated that high HBsAg titer in IT/CHB induced Arg1+ MDSC. Furthermore, elevated serum TNF‐α and IL‐4 in CHB potentiated Arg1/PD‐L1/CD40/CTLA‐4 expression, whereas increased IL‐1β in CHB/IC triggered the expansion of PD‐L1+ MDSCs and iNOS+ MDSCs. MDSCs, sorted from CHB/IC, greatly attenuated IL‐2/interferon gamma (IFN‐γ) production by HBV‐specific CD8+/CD4+ T cells, the effect being more pronounced in CHB. However, MDSCs of IT minimally affected the cytokine production by T cells. Adding Arg1‐/iNOS‐inhibitor restored only IFN‐γ production, while neutralizing PD‐L1 recovered both IL‐2 and IFN‐γ secretion by T cells. Moreover, MDSCs from IT/CHB disrupted virus‐specific T‐cell trafficking by down‐regulating chemokine receptor type 5 on them via TGF‐β signaling. One year of tenofovir therapy failed to normalize MDSC phenotype and HBV‐specific T‐cell response. Conclusions Diversity of MDSCs during CHI affects HBV‐specific T‐cell response and homing. Hence, therapeutic targeting of MDSCs could boost anti‐HBV immunity.

Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis

“…MDSC phenotypes and function appear to dynamically change over time in different stages of HBV infection ( 60 ). Profound suppressive activities, including expression of Arginase, iNOS and PD-L1 are seen in active CHB, but much weaker suppressive functions, expressing only arginase, in the IT state ( 152 ). PMN-MDSCs expand transiently in acute HBV and are increased most in disease states with high viral replication but low levels of immune-mediated inflammation ( 60 ).…”

“…In a mouse model, chemokine receptor CCR9 in M-MDSCs is induced by HBsAg via ERK/IL-6 pathway, and CCR9-CCL25 interaction mediates Gr1 + Ly6C high Ly6G - M-MDSCs homing to the thymus, where HBsAg-specific CD8 + CD4 - T cells are killed by NOX1-expressing M-MDSCs ( 162 ). Another HBV-specific mechanism involves impaired CCR5-CCL5 interaction by TGF-β released from MDSCs, which affects the migration of HBV-specific T cells to the liver ( 152 , 163 , 164 ). This effect is seen during active hepatitis, but not during IT or after viral clearance ( 152 ).…”

“…Another HBV-specific mechanism involves impaired CCR5-CCL5 interaction by TGF-β released from MDSCs, which affects the migration of HBV-specific T cells to the liver ( 152 , 163 , 164 ). This effect is seen during active hepatitis, but not during IT or after viral clearance ( 152 ).…”

Abnormally primed CD8 T cells: The Achilles’ heel of CHB

“…For chronic hepatitis B virus infection, prolonged exposure to HBV virus or HBsAg/hepatitis B e antigen (HBeAg) may result in the inability of APCs to provide adequate signals 1 and 2 for T-cell priming (25,26). Combined with the lack of activating cytokines (27) and the interference of inhibitory molecules (28,29), it may ultimately lead to the dysfunction of HBV-specific CD8 T cells (Figure 2).…”

“…Through the expression of Arg1 (76) or PD-1-induced IL-10 (77), MDSCs have been demonstrated to impair the HBV-specific T-cell response during the immune-tolerance phase of chronic infection. In addition, MDSCs from CHB patients could downregulate chemokine receptors via TGF-b signalling (29) to affect virus-specific T-cell homing. As anti-inflammatory cytokines, IL-10 and TGF-b perform indispensable roles in virus-related immune evasion.…”