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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1509874
This article is part of the Research Topic Mechanisms and Therapeutic Opportunities of T Cell Impairment in Cancer Immunity and Immunotherapy View all 5 articles

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

Provisionally accepted
Ling Li Ling Li 1Manzhi Zhao Manzhi Zhao 1,2Marjan Van Meurs Marjan Van Meurs 1Inge Brouwers-Haspels Inge Brouwers-Haspels 1Renske J.H. Den Dekker Renske J.H. Den Dekker 1Merel E.P. Wilmsen Merel E.P. Wilmsen 1Dwin G.B. Grashof Dwin G.B. Grashof 1Harmen Jan George van de Werken Harmen Jan George van de Werken 1Shringar Rao Shringar Rao 3Casper Rokx Casper Rokx 4Yvonne M. Mueller Yvonne M. Mueller 1Peter D. Katsikis Peter D. Katsikis 1*
  • 1 Department of Immunology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands, Rotterdam, Netherlands
  • 2 Current address: Department of Pulmonary and Critical Care Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University., Guangzhou, China
  • 3 Department of Biochemistry, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, Netherlands
  • 4 Department of Internal Medicine, and Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, Netherlands

The final, formatted version of the article will be published soon.

    HIV-specific-CD8+ T cells are exhausted in people with HIV (PWH) with diminished proliferative potential and defective cytokine production. The exhaustion state of those cells hinders effective immune response against HIV infection. We found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. By utilizing an in vitro murine T cell exhaustion system, we found bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptors expression of exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were further 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. These data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. Taken together, our data indicate that bryostatin-1 may have the potential to enhance exhausted CD8+ T cell responses, which are crucial in chronic infection or cancer.

    Keywords: Bryostatin-1, exhausted CD8+ T cells, HIV, MAP Kinase 11, IFN-γ production

    Received: 11 Oct 2024; Accepted: 19 Dec 2024.

    Copyright: © 2024 Li, Zhao, Meurs, Brouwers-Haspels, Den Dekker, Wilmsen, Grashof, van de Werken, Rao, Rokx, Mueller and Katsikis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Peter D. Katsikis, Department of Immunology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands, Rotterdam, Netherlands

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.