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.
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.
Abstract. The paper proposes the use of the Silhouette Coefficient (SC) as a ranking measure to perform instance selection in text classification. Our selection criterion was to keep instances with mid-range SC values while removing the instances with high and low SC values. We evaluated our hypothesis across three well-known datasets and various machine learning algorithms. The results show that our method helps to achieve the best trade-off between classification accuracy and training time.
During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28− T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28− T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28− T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28− T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28− T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28− T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28− T-cell killing. Both CD28+ and CD28− T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28− T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28− T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28− T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28− T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.
Chronic HBV infection (CHI) is a major cause of end-stage liver disease for which pharmacological treatments currently available are inadequate. Chronically HBV-infected patients fail to mount an efficient immune response to the virus, impeding viral clearance and recovery from hepatitis.
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