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 7

CD38 inhibition restores metabolic dysregulation and improves functionality of CMV-specific CD8+ T cells in noncontrollers.

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CD38 inhibition restores metabolic dysregulation and improves functional...
(A–H) PBMCs were stimulated with pp65495–503 peptide for either 20 hours (short stimulation) or 6 days (long stimulation). (A) H3K27me3 levels in long-stimulated pp65495–503–specific CD8+ T cells from noncontrollers (n = 7) in presence of vehicle, CD38i, or CD38i + Ex527. (B and C) Representative contour plot (B) and quantitative graphs (C) show MTDR and TMRM staining of pp65495–503–specific CD8+ T cells after short stimulation in the presence or absence of CD38i (n = 7/group). (D and E) Representative histogram (D) and quantitative graphs (E) show PKM expression of pp65495–503–specific CD8+ T cells after long stimulation in presence or absence of CD38i (n = 5–6/group). (F) Expression of PGC-1α in long-stimulated pp65495–503–specific CD8+ T cells from noncontrollers (n = 7) in presence of vehicle, CD38i, or CD38i + Ex527. (G and H) ATP5a and cytochrome c expression (G) and cumulative ETC protein expression (cytochrome c/SDHA/ATP5a) (H) after long stimulation in presence or absence of CD38i (n = 5–6/group). (I and J) After short stimulation, cytokine production was measured by intracellular cytokine staining in presence or absence of CD38i. Representative CD137 versus IFN-γ staining (I), percentage IFN-γ+CD137+ of pp65495–503–specific CD8+ T cells (n = 7/group) (J). (K) Percentage IFN-γ+CD137+ cells of pp65495–503–specific CD8+ T cells from noncontrollers after long stimulation with peptide in presence of vehicle, etomoxir, or etomoxir plus CD38i (n = 5). (L) PBMCs were cultured in presence of CD38i or vehicle for 16 hours, followed by stimulation with pp65495–503 peptide for 4 hours. Subsequently, SCENITH was performed on CD137+CD69+CD8+ T cells (n = 4 noncontrollers). Data are presented as mean ± SEM. Each symbol represents an individual. Statistical analysis by paired t test or repeated-measures ANOVA with Geisser-Greenhouse correction. *P < 0.05; **P < 0.01; ***P < 0.001.