Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11
IntroductionBryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminati...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1509874/full |
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| author | Ling Li Manzhi Zhao Marjan van Meurs Inge Brouwers-Haspels Renske J. H. den Dekker Merel E. P. Wilmsen Dwin G. B. Grashof Harmen J. G. van de Werken Shringar Rao Casper Rokx Yvonne M. Mueller Peter D. Katsikis |
| author_facet | Ling Li Manzhi Zhao Marjan van Meurs Inge Brouwers-Haspels Renske J. H. den Dekker Merel E. P. Wilmsen Dwin G. B. Grashof Harmen J. G. van de Werken Shringar Rao Casper Rokx Yvonne M. Mueller Peter D. Katsikis |
| author_sort | Ling Li |
| collection | DOAJ |
| description | IntroductionBryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.MethodsPBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established in vitro murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.ResultsWe found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of in vitro generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-γ production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.DiscussionOur data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells. |
| format | Article |
| id | doaj-art-18c0c593b68d44e59b69ffdbf363a083 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-18c0c593b68d44e59b69ffdbf363a0832025-01-14T05:10:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15098741509874Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11Ling Li0Manzhi Zhao1Marjan van Meurs2Inge Brouwers-Haspels3Renske J. H. den Dekker4Merel E. P. Wilmsen5Dwin G. B. Grashof6Harmen J. G. van de Werken7Shringar Rao8Casper Rokx9Yvonne M. Mueller10Peter D. Katsikis11Department of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Internal Medicine, and Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Immunology, Erasmus University Medical Center, Rotterdam, NetherlandsIntroductionBryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.MethodsPBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established in vitro murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.ResultsWe found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of in vitro generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-γ production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.DiscussionOur data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1509874/fullbryostatin-1exhausted CD8+ T cellsHIVMAP kinase 11IFN-γ production |
| spellingShingle | Ling Li Manzhi Zhao Marjan van Meurs Inge Brouwers-Haspels Renske J. H. den Dekker Merel E. P. Wilmsen Dwin G. B. Grashof Harmen J. G. van de Werken Shringar Rao Casper Rokx Yvonne M. Mueller Peter D. Katsikis Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 Frontiers in Immunology bryostatin-1 exhausted CD8+ T cells HIV MAP kinase 11 IFN-γ production |
| title | Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 |
| title_full | Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 |
| title_fullStr | Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 |
| title_full_unstemmed | Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 |
| title_short | Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11 |
| title_sort | bryostatin 1 enhances the proliferation and functionality of exhausted cd8 t cells by upregulating map kinase 11 |
| topic | bryostatin-1 exhausted CD8+ T cells HIV MAP kinase 11 IFN-γ production |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1509874/full |
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