Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8⁺ T cell functionality and metabolism

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Abstract

Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in immunocompromised individuals such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in immunosuppressed individuals have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in immunocompromised patients and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with non-controlled 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+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hypo-responsiveness in individuals who fail to control chronic viral infection.

Authors

Nils Mülling, Felix M. Behr, Graham A. Heieis, Kristina Boss, Suzanne van Duikeren, Floortje J. van Haften, Iris N. Pardieck, Esmé T.I. van der Gracht, Ward Vleeshouwers, Tetje C. van der Sluis, J. Fréderique de Graaf, Dominique M.B. Veerkamp, Kees L.M.C. Franken, Xin Lei, Lukas van de Sand, Sjoerd H. van der Burg, Marij J.P. Welters, Sebastiaan Heidt, Wesley Huisman, Simon P. Jochems, Martin Giera, Oliver Witzke, Aiko P.J. de Vries, Andreas Kribben, Bart Everts, Benjamin Wilde, Ramon Arens