Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11

Bryostatin-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 reactivat...

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Published in:	Frontiers in immunology Vol. 15; p. 1509874
Main Authors:	Li, Ling, Zhao, Manzhi, van Meurs, Marjan, Brouwers-Haspels, Inge, den Dekker, Renske J. H., Wilmsen, Merel E. P., Grashof, Dwin G. B., van de Werken, Harmen J. G., Rao, Shringar, Rokx, Casper, Mueller, Yvonne M., Katsikis, Peter D.
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media SA 14.01.2025 Frontiers Media S.A
Subjects:	Animals bryostatin-1 Bryostatins - pharmacology Cancer Cancer immunotherapy Cancer therapies CD8 antigen CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell growth Cell proliferation Cell Proliferation - drug effects Chronic infection Clinical trials Cytotoxicity Down-regulation exhausted CD8+ T cells Flow cytometry Hepatocyte nuclear factor 1 HIV HIV Infections - drug therapy HIV Infections - immunology HIV-1 - immunology Human immunodeficiency virus Humans IFN-γ production Immunity (Disease) Immunology Infections Kinases Lymphocyte Activation - drug effects Lymphocytes Lymphocytes T MAP kinase MAP kinase 11 Mice PD-1 protein Peptides Protein kinase C Proteins Ribonucleic acid RNA Sequence analysis Transcription factors Up-Regulation γ-Interferon HIV bryostatin-1 IFN-γ production exhausted CD8+ T cells MAP kinase 11
ISSN:	1664-3224, 1664-3224
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Summary:	Bryostatin-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. PBMCs 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 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. We 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 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. Our 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Edited by: Raquel Alarcon Rodriguez, University of Almeria, Spain Reviewed by: Hiroki Ishikawa, Yasuda Women’s University, Japan Present address: Manzhi Zhao, Department of Pulmonary and Critical Care Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China These authors have contributed equally to this work Kenji Sugata, Kumamoto University, Japan
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2024.1509874