{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:33:05Z","timestamp":1790940785355,"version":"4.1.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Patients with chronic HBV infection (CHI) exhibit defective anti-viral immune-response whose underlying causes still remain unclear. Monocytes act as immune sentinels for pathogens and can regulate immunity via interaction with other immune-cells, apart from differentiating into macrophages. Immune-checkpoint molecules (ICMs) expressed by immune-cells, including monocytes are known to negatively regulate immune-responses. Here, we evaluated the expression of ICMs, namely, Gal-9, PD-L1, and CTLA-4 on monocytes in different phases of CHI, identified the viral and the host factors causing their aberrant expression and investigated their impact during interaction of monocytes with T-cells, B-cells and NK-cells and also on monocyte to macrophage differentiation. Influence of Tenofovir therapy on the expression of monocytic ICMs was also studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Collection of blood and liver-tissue samples from HBV infected patients and controls, flow-cytometry, cell sorting, cell culture and immune-fluorescence were performed for this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gal-9<jats:sup>+<\/jats:sup> and PD-L1<jats:sup>+<\/jats:sup>-monocytes were significantly increased in HBeAg-positive as well as HBeAg-negative chronic hepatitis B (CHB) patients than healthy controls (HC). In immune-tolerant (IT) subjects, only Gal-9<jats:sup>+<\/jats:sup>-monocytes and in inactive carriers (IC), PD-L1<jats:sup>+<\/jats:sup>-monocytes were higher than HC while CTLA-4<jats:sup>+<\/jats:sup>-monocytes remained comparable among groups. High serum Hepatitis B surface antigen (HBsAg) concentration in CHB as well as IT and TNF-\u03b1 in CHB triggered monocytic Gal-9-expression whereas, PD-L1 was induced by elevated TNF-\u03b1 and IL-4 in CHB and IL-1\u03b2 in CHB and IC. Purified monocytes from CHB and IT having high Gal-9 expression led to expansion of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>FOXP3<jats:sup>+<\/jats:sup>-Tregs, CD19<jats:sup>+<\/jats:sup>IL-10<jats:sup>+<\/jats:sup>-Bregs and CD19<jats:sup>+<\/jats:sup>CD27<jats:sup>-<\/jats:sup>CD21<jats:sup>\u2013<\/jats:sup>atypical memory B-cells and these monocytes also preferentially differentiated into M2-macrophages. These phenomena were reversed by anti-Gal-9-antibody. Parallelly, PD-L1<jats:sup>+<\/jats:sup>-monocytes in CHB and IC reduced IL-2\/IFN-\u03b3 and IL-6 production by HBV-specific T- and B-cells respectively, which were restored by anti-PD-L1-antibody. Both Gal-9<jats:sup>+<\/jats:sup>- and PD-L1<jats:sup>+<\/jats:sup>-monocytes caused decline in IFN-\u03b3<jats:sup>+<\/jats:sup>-NK-cells but enhanced IL-10-expressing HBV-specific-T-cells and NK-cells. Increased intrahepatic CD14<jats:sup>+<\/jats:sup>Gal-9<jats:sup>+<\/jats:sup> and CD14<jats:sup>+<\/jats:sup>PD-L1<jats:sup>+<\/jats:sup>-monocytes were noted in CHB patients than HC. One-year tenofovir therapy failed to reduce monocytic Gal-9 and PD-L1 along with the levels of HBsAg, TNF-\u03b1, IL-1\u03b2 and IL-4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Monocytic Gal-9 and PD-L1, expressed heterogeneously in different phases of CHI, exert diverse inhibitory effects on immune-responses and their therapeutic targeting could boost anti-HBV immunity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1474853","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T04:26:54Z","timestamp":1728448014000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Monocyte-derived Galectin-9 and PD-L1 differentially impair adaptive and innate immune response in chronic HBV infection and their expression remain unaltered after antiviral 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