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

被引:0
作者
Li, Ling [1 ]
Zhao, Manzhi [1 ,5 ]
van Meurs, Marjan [1 ]
Brouwers-Haspels, Inge [1 ]
den Dekker, Renske J. H. [1 ]
Wilmsen, Merel E. P. [1 ]
Grashof, Dwin G. B. [1 ]
van de Werken, Harmen J. G. [1 ]
Rao, Shringar [2 ]
Rokx, Casper [3 ,4 ]
Mueller, Yvonne M. [1 ]
Katsikis, Peter D. [1 ]
机构
[1] Erasmus MC, Dept Immunol, Rotterdam, Netherlands
[2] Erasmus MC, Dept Biochem, Rotterdam, Netherlands
[3] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
[4] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
[5] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Pulm & Crit Care Med, Guangzhou, Guangdong, Peoples R China
来源
FRONTIERS IN IMMUNOLOGY | 2025年 / 15卷
基金
中国国家自然科学基金;
关键词
bryostatin-1; exhausted CD8+T cells; HIV; MAP kinase 11; IFN-gamma production; CD8(+) T-CELLS; ACTIVATED PROTEIN-KINASE; PHASE-II TRIAL; ANTINEOPLASTIC AGENT; CYTOKINE PRODUCTION; HIV-1; MODULATION; EXPRESSION; INFECTION; IL-2;
D O I
10.3389/fimmu.2024.1509874
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Introduction 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.Methods 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 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.Results 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 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-gamma production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.Discussion 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.
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