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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1474853
Monocyte-derived Galectin-9 and PD-L1 differentially impair adaptive and innate
Provisionally accepted- Institute of Post Graduate Medical Education And Research (IPGMER), Kolkata, India
Introduction: 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. Methods: 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. Results: Gal-9+ and PD-L1+-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+-monocytes and in inactive carriers (IC), PD-L1+-monocytes were higher than HC while CTLA-4+-monocytes remained comparable among groups. High serum Hepatitis B surface antigen (HBsAg) concentration in CHB as well as IT and TNF-α in CHB triggered monocytic Gal-9-expression whereas, PD-L1 was induced by elevated TNF-α and IL-4 in CHB and IL-1β in CHB and IC. Purified monocytes from CHB and IT having high Gal-9 expression led to expansion of CD4+CD25+FOXP3+-Tregs, CD19+IL-10+-Bregs and CD19+CD27-CD21--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+-monocytes in CHB and IC reduced IL-2/IFN-γ and IL-6 production by HBV-specific T- and B-cells respectively, which were restored by anti-PD-L1-antibody. Both Gal-9+- and PD-L1+-monocytes caused decline in IFN-γ+-NK-cells but enhanced IL-10-expressing HBV-specific-T-cells and NK-cells. Increased intrahepatic CD14+Gal-9+ and CD14+PD-L1+-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-α, IL-1β and IL-4. Conclusions: 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.
Keywords: immune checkpoint molecules, chronically HBV-infected patients, Host and viral factors, Immunosuppression, tenofovir
Received: 02 Aug 2024; Accepted: 18 Sep 2024.
Copyright: © 2024 Dey, Biswas, Pal, Nandi, Khatun, Jha, Chakraborty, Baidya, Ghosh, Banerjee, Ahammed, Chowdhury and Datta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Simanti Datta, Institute of Post Graduate Medical Education And Research (IPGMER), Kolkata, India
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