The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses
Specific CD8+ T cells are crucial for the control of viruses. However, during many chronic viral infections these cells become dysfunctional. Immune checkpoint receptors, like PD-1 expressed on CD8+ T cells, contribute to this functional suppression during chronic infection. However, during the acut...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Virology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fviro.2022.836291/full |
| _version_ | 1828879726363541504 |
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| author | Paul David Paul David Jaana Westmeier Malgorzata Drabczyk-Pluta Tanja Werner Julia Ickler Sandra Francois Wibke Bayer Kathrin Sutter Maria Luisa Del Rio Jose-Ignacio Rodriguez-Barbosa Ulf Dittmer Gennadiy Zelinskyy |
| author_facet | Paul David Paul David Jaana Westmeier Malgorzata Drabczyk-Pluta Tanja Werner Julia Ickler Sandra Francois Wibke Bayer Kathrin Sutter Maria Luisa Del Rio Jose-Ignacio Rodriguez-Barbosa Ulf Dittmer Gennadiy Zelinskyy |
| author_sort | Paul David |
| collection | DOAJ |
| description | Specific CD8+ T cells are crucial for the control of viruses. However, during many chronic viral infections these cells become dysfunctional. Immune checkpoint receptors, like PD-1 expressed on CD8+ T cells, contribute to this functional suppression during chronic infection. However, during the acute phase of infection virus-specific CD8+ T cells express high levels of PD-1 but are fully competent in killing virus-infected cells and there is increasing evidence that the biological activity of inhibitory receptors is strongly influenced by the availability of their respective ligands. We determined the expression of ligands for inhibitory receptors on infected myeloid cells during the acute phase of Friend retroviral (FV) infection. FV infection of granulocytes, monocytes, and macrophages strongly increased the cell surface expression of PD-L1 and the recently described ligand HVEM for inhibitory receptors BTLA and CD160. In addition, the infection of human myeloid cells in vitro with HIV also enhanced the expression of PD-L1 and HVEM. In infected mice, the upregulation of inhibitory ligands on infected cells was accompanied by enhanced frequencies of FV-specific CD8+ T cells that express PD-1, and the inhibitory receptors CD160 and BTLA. To define the functional effects of HVEM on activated CD8+ T cells, FV-infected mice were treated with blocking antibodies that prevented the interaction of HVEM with its two receptors, CD160 or BTLA, alone or in combination with anti-PD-L1 antibodies. Blocking the interaction of HVEM with CD160 and BTLA improved the production of cytotoxic molecules and the elimination of FV-infected cells. This effect was augmented when the therapy was combined with anti-PD-L1 antibodies, resulting in an additional expansion of cytotoxic CD8+ T cells. Thus, the ligand HVEM for the inhibitory receptors CD160 and BTLA downregulates the functionality of CD8+ T cells during retroviral infection and are potential targets for the immunomodulatory therapy of chronic viral infections. |
| first_indexed | 2024-12-13T09:33:59Z |
| format | Article |
| id | doaj.art-b159ccee1050406998b106e8b901a932 |
| institution | Directory Open Access Journal |
| issn | 2673-818X |
| language | English |
| last_indexed | 2024-12-13T09:33:59Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Virology |
| spelling | doaj.art-b159ccee1050406998b106e8b901a9322022-12-21T23:52:25ZengFrontiers Media S.A.Frontiers in Virology2673-818X2022-03-01210.3389/fviro.2022.836291836291The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell ResponsesPaul David0Paul David1Jaana Westmeier2Malgorzata Drabczyk-Pluta3Tanja Werner4Julia Ickler5Sandra Francois6Wibke Bayer7Kathrin Sutter8Maria Luisa Del Rio9Jose-Ignacio Rodriguez-Barbosa10Ulf Dittmer11Gennadiy Zelinskyy12Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyDepartment of Surgery, Friedrich-Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyTransplantation Immunobiology and Immunotherapy Section, Institute of Molecular Biology, Genomics and Proteomics, University of Leon, Leon, SpainTransplantation Immunobiology and Immunotherapy Section, Institute of Molecular Biology, Genomics and Proteomics, University of Leon, Leon, SpainInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, GermanySpecific CD8+ T cells are crucial for the control of viruses. However, during many chronic viral infections these cells become dysfunctional. Immune checkpoint receptors, like PD-1 expressed on CD8+ T cells, contribute to this functional suppression during chronic infection. However, during the acute phase of infection virus-specific CD8+ T cells express high levels of PD-1 but are fully competent in killing virus-infected cells and there is increasing evidence that the biological activity of inhibitory receptors is strongly influenced by the availability of their respective ligands. We determined the expression of ligands for inhibitory receptors on infected myeloid cells during the acute phase of Friend retroviral (FV) infection. FV infection of granulocytes, monocytes, and macrophages strongly increased the cell surface expression of PD-L1 and the recently described ligand HVEM for inhibitory receptors BTLA and CD160. In addition, the infection of human myeloid cells in vitro with HIV also enhanced the expression of PD-L1 and HVEM. In infected mice, the upregulation of inhibitory ligands on infected cells was accompanied by enhanced frequencies of FV-specific CD8+ T cells that express PD-1, and the inhibitory receptors CD160 and BTLA. To define the functional effects of HVEM on activated CD8+ T cells, FV-infected mice were treated with blocking antibodies that prevented the interaction of HVEM with its two receptors, CD160 or BTLA, alone or in combination with anti-PD-L1 antibodies. Blocking the interaction of HVEM with CD160 and BTLA improved the production of cytotoxic molecules and the elimination of FV-infected cells. This effect was augmented when the therapy was combined with anti-PD-L1 antibodies, resulting in an additional expansion of cytotoxic CD8+ T cells. Thus, the ligand HVEM for the inhibitory receptors CD160 and BTLA downregulates the functionality of CD8+ T cells during retroviral infection and are potential targets for the immunomodulatory therapy of chronic viral infections.https://www.frontiersin.org/articles/10.3389/fviro.2022.836291/fullimmunoregulationretrovirusCD160BTLAHVEMPD-L1 |
| spellingShingle | Paul David Paul David Jaana Westmeier Malgorzata Drabczyk-Pluta Tanja Werner Julia Ickler Sandra Francois Wibke Bayer Kathrin Sutter Maria Luisa Del Rio Jose-Ignacio Rodriguez-Barbosa Ulf Dittmer Gennadiy Zelinskyy The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses Frontiers in Virology immunoregulation retrovirus CD160 BTLA HVEM PD-L1 |
| title | The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses |
| title_full | The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses |
| title_fullStr | The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses |
| title_full_unstemmed | The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses |
| title_short | The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses |
| title_sort | role of the inhibitory ligand hvem and its receptors cd160 and btla in the regulation of anti retroviral t cell responses |
| topic | immunoregulation retrovirus CD160 BTLA HVEM PD-L1 |
| url | https://www.frontiersin.org/articles/10.3389/fviro.2022.836291/full |
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