1. Inhibiting the NADase CD38 improves cytomegalovirus-specific [CD8.sup.+] T cell functionality and metabolism
- Author
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Mulling, Nils, Behr, Felix M., Heieis, Graham A., Boss, Kristina, van Duikeren, Suzanne, van Haften, Floortje J., Pardieck, Iris N., van der Gracht, Esme T.I., Vleeshouwers, Ward, van der Sluis, Tetje C., de Graaf, J. Frederique, Veerkamp, Dominique M.B., Franken, Kees L.M.C., Lei, Xin, van de Sand, Lukas, van der Burg, Sjoerd H., Welters, Marij J.P., Heidt, Sebastiaan, Huisman, Wesley, Jochems, Simon P., Giera, Martin, Witzke, Oliver, de Vries, Aiko P.J., Kribben, Andreas, Everts, Bart, Wilde, Benjamin, and Arens, Ramon
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Physiological aspects ,Health aspects ,CD8 lymphocytes -- Health aspects ,Glycoproteins -- Health aspects ,Medical research ,Metabolism -- Health aspects ,Cytomegalovirus infections -- Physiological aspects ,Medicine, Experimental - Abstract
Introduction Human cytomegalovirus (CMV) is one of the most encountered opportunistic viral pathogens in kidney transplant recipients (KTRs) (1). Although major advances in the treatment and prophylaxis of CMV-associated complications [...], Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in people who are immunocompromised, such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in people who are immunosuppressed have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific [CD8.sup.+] T cells in patients who are immunocompromised and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific [CD8.sup.+] T cells in KTRs with noncontrolled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific [CD8.sup.+] T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of [CD8.sup.+] T cells could be targeted by inhibiting CD38 to reverse hyporesponsiveness in individuals who fail to control chronic viral infection.
- Published
- 2024
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