Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism
Nils Mülling, … , Benjamin Wilde, Ramon Arens
Nils Mülling, … , Benjamin Wilde, Ramon Arens
Published July 2, 2024
Citation Information: J Clin Invest. 2024;134(17):e179561. https://doi.org/10.1172/JCI179561.
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Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism

Abstract

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+ 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+ 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+ 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 hyporesponsiveness 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

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Figure 4

Impaired glycolytic responsiveness and increased FAO dependency of antigen-stimulated CMV-specific CD8+ T cells in noncontrollers.

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Impaired glycolytic responsiveness and increased FAO dependency of antig...
(A–I) PBMCs were stimulated with pp65495–503 peptide for either 20 hours (short stimulation) or 6 days (long stimulation). (A) Relative change in gMFI to unstimulated condition of GLUT1 and PKM expression of pp65495–503–specific CD8+ T cells after long stimulation (n = 4–7/group). (B) After short stimulation, supernatant was collected for the analysis of cytokine and granzyme production. Cells were either cultured in presence of 2-DG or not. The percentage decrease in cytokine concentration (pg/mL) after 2-DG treatment is shown (n = 5/group). (C and D) Relative change (to unstimulated condition) of G6PD and CD98 expression (C), ATP5a, cytochrome c, and SDHA expression (D) of pp65495–503–specific CD8+ T cells after long stimulation (n = 4–7/group). (E) Relative change (to unstimulated condition) of MitoSOX, MTDR, and TMRM of pp65495–503–specific CD8+ T cells after short stimulation (n = 4–7/group). (F) Cells were long stimulated and cultured either in the presence or absence of 2-DG. The percentage decrease of TMRM in CD137+CD8+ T cells by 2-DG treatment is shown. (G) Cells were long stimulated in presence or absence of oligomycin. Relative change (stimulated/stimulated + oligomycin) of TMRM uptake in CD137+CD8+ T cells (n = 4–7/group). (H) Relative change (to unstimulated condition) of CPT1a and MCAD expression of pp65495–503–specific CD8+ T cells after long stimulation (n = 4–7/group). (I) After short stimulation, cytokine production was measured by intracellular cytokine staining. Percentage decrease of CD137+IFN-γ+ cells (of total CD8+ T cells) in the presence of etomoxir (n = 4–5/group). (J) SCENITH of CD137+CD69+CD8+ T cells after 4 hours of stimulation with pp65495–503 peptide (n = 4/group). Data are presented as mean ± SEM. Each symbol represents an individual. Statistical analysis by 2-sided student’s t test or 1-way ANOVA with Tukey’s test for multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.