Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways
Abstract Background Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infe...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04104-8 |
| _version_ | 1797840869635653632 |
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| author | Arshi Khanam Alip Ghosh Joel V. Chua Shyam Kottilil |
| author_facet | Arshi Khanam Alip Ghosh Joel V. Chua Shyam Kottilil |
| author_sort | Arshi Khanam |
| collection | DOAJ |
| description | Abstract Background Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. Methods We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. Results CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. Conclusions CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB. |
| first_indexed | 2024-04-09T16:21:47Z |
| format | Article |
| id | doaj.art-9737ea0b17fb4ad5b1b30e9066e403b6 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T16:21:47Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-9737ea0b17fb4ad5b1b30e9066e403b62023-04-23T11:26:48ZengBMCJournal of Translational Medicine1479-58762023-04-0121111610.1186/s12967-023-04104-8Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathwaysArshi Khanam0Alip Ghosh1Joel V. Chua2Shyam Kottilil3Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of MedicineDivision of Clinical Care and Research, Institute of Human Virology, University of Maryland School of MedicineDivision of Clinical Care and Research, Institute of Human Virology, University of Maryland School of MedicineDivision of Clinical Care and Research, Institute of Human Virology, University of Maryland School of MedicineAbstract Background Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. Methods We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. Results CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. Conclusions CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB.https://doi.org/10.1186/s12967-023-04104-8CHBCCR4CD4 and CD8 T cellsTregs |
| spellingShingle | Arshi Khanam Alip Ghosh Joel V. Chua Shyam Kottilil Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways Journal of Translational Medicine CHB CCR4 CD4 and CD8 T cells Tregs |
| title | Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways |
| title_full | Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways |
| title_fullStr | Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways |
| title_full_unstemmed | Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways |
| title_short | Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways |
| title_sort | blockade of ccr4 breaks immune tolerance in chronic hepatitis b patients by modulating regulatory pathways |
| topic | CHB CCR4 CD4 and CD8 T cells Tregs |
| url | https://doi.org/10.1186/s12967-023-04104-8 |
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