Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism
Nils Mülling1,2, Felix M Behr1, Graham A Heieis3
1Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.
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.
Insights
Cytomegalovirus (CMV) infection impairs CD8+ T cell metabolism in kidney transplant recipients. Inhibiting CD38 revitalized these immune cells, improving their ability to fight the virus.
Area of Science:
- Immunology
- Virology
- Metabolism
Background:
- Cytomegalovirus (CMV) is a significant opportunistic pathogen in immunocompromised individuals, particularly kidney transplant recipients (KTRs).
- The precise mechanisms limiting T cell effectiveness against CMV in immunosuppressed patients remain unclear.
Purpose of the Study:
- To investigate the metabolic state of CMV-specific CD8+ T cells in KTRs with uncontrolled CMV infection.
- To identify therapeutic targets for restoring anti-CMV immune responses.
Main Methods:
- In-depth metabolic profiling of CMV-specific CD8+ T cells from KTRs.
- Analysis of transcriptional, protein, and functional levels of T cells.
- Inhibition of CD38 activity in vitro and in a mouse model of CMV infection.
Main Results:
- CMV-specific CD8+ T cells in KTRs exhibit metabolic dysregulation, including impaired glycolysis and increased mitochondrial stress.
- Elevated expression of nicotinamide adenine dinucleotide nucleotidase (NADase) CD38 was observed.
- Inhibiting CD38 restored T cell metabolism and enhanced cytokine production.
- Findings were validated in a mouse model of immunosuppressed CMV infection.
Conclusions:
- Metabolic dysfunction in CD8+ T cells contributes to uncontrolled CMV infection in KTRs.
- Targeting CD38 offers a potential strategy to reverse T cell hyporesponsiveness and improve viral control in immunocompromised individuals.
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