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

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 8

Mouse model of CMV infection confirms an increased CD38 expression on CMV-specific CD8+ T cells and association with metabolic alterations.

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Mouse model of CMV infection confirms an increased CD38 expression on CM...
(A–F) C57BL/6 mice were infected with MCMV-Smith (2 × 104 PFU). Mice received immunosuppression (IS) medication (tacrolimus + dexamethasone) starting on day 3 after MCMV challenge (IS+, n = 7) or were untreated (IS–, n = 7). On day 20 salivary glands and spleens were isolated for determination of viral load and metabolic state of MCMV-specific CD8+ T cells, respectively. (A) Experimental setup. Created with biorender.com. (B) MCMV load in salivary glands. (C) Frequency of M38316–323–specific CD8+ T cells. (D) CD38 expression on M38316–323–specific CD8+ T cells. (E) GLUT1, PKM, ATP5a, and MTDR levels of M38316–323–specific CD8+ T cells from IS– and IS+ mice. (F) GLUT1, PKM, ATP5a, and MTDR levels in CD38lo and CD38hi M38316–323–specific CD8+ T cells from IS+ mice. (G–M) C57BL/6 mice were infected with MCMV-Smith and received immunosuppression as above. On day 20, 1 group received CD38i twice daily for 7 consecutive days (n = 12) while the another (control) group received vehicle (n = 11). On day 27 livers and spleens were isolated for determination of viral load and metabolic state of MCMV-specific CD8+ T cells, respectively. (G) MCMV load in livers. (H) Weight difference before and after CD38i treatment. (I) Total splenocyte count. (J) Frequency of M38316–323–specific cells. (K) CD38 expression on M38316–323–specific CD8+ T cells. (L) Percentage IFN-γ+ and IFN-γ+TNF+ cells of total CD8+ T cells after stimulation for 5 hours with peptide. (M) Metabolic protein expression of M38316–323–specific CD8+ T cells. Data are presented as mean ± SEM. Each symbol represents an individual. Statistical analysis by 2-sided t test, paired t test, or Mann-Whitney U test (viral load). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.