The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections
Summary: Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell s...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471931664X |
| _version_ | 1818444675235708928 |
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| author | Eri Katsuyama Abel Suarez-Fueyo Sean J. Bradley Masayuki Mizui Ana V. Marin Lama Mulki Suzanne Krishfield Fabio Malavasi Joon Yoon Shannan J. Ho Sui Vasileios C. Kyttaris George C. Tsokos |
| author_facet | Eri Katsuyama Abel Suarez-Fueyo Sean J. Bradley Masayuki Mizui Ana V. Marin Lama Mulki Suzanne Krishfield Fabio Malavasi Joon Yoon Shannan J. Ho Sui Vasileios C. Kyttaris George C. Tsokos |
| author_sort | Eri Katsuyama |
| collection | DOAJ |
| description | Summary: Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically. : Katsuyama et al. find that an expanded CD8CD38high T cell population in SLE patients is linked to infections. CD8CD38high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD+/Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. Keywords: systemic lupus erythematosus, patients, CD8 T cell, CD38, cytotoxicity, infection, nicotinamide adenine dinucleotide, Sirtuin1, EZH2 |
| first_indexed | 2024-12-14T19:19:42Z |
| format | Article |
| id | doaj.art-a9af69c5ef994507a2ab02f4b9f4a91f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T19:19:42Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-a9af69c5ef994507a2ab02f4b9f4a91f2022-12-21T22:50:23ZengElsevierCell Reports2211-12472020-01-01301112123.e4The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to InfectionsEri Katsuyama0Abel Suarez-Fueyo1Sean J. Bradley2Masayuki Mizui3Ana V. Marin4Lama Mulki5Suzanne Krishfield6Fabio Malavasi7Joon Yoon8Shannan J. Ho Sui9Vasileios C. Kyttaris10George C. Tsokos11Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USALaboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, University of Torino, and Fondazione Ricerca Molinette, Torino, ItalyHarvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USAHarvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically. : Katsuyama et al. find that an expanded CD8CD38high T cell population in SLE patients is linked to infections. CD8CD38high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD+/Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. Keywords: systemic lupus erythematosus, patients, CD8 T cell, CD38, cytotoxicity, infection, nicotinamide adenine dinucleotide, Sirtuin1, EZH2http://www.sciencedirect.com/science/article/pii/S221112471931664X |
| spellingShingle | Eri Katsuyama Abel Suarez-Fueyo Sean J. Bradley Masayuki Mizui Ana V. Marin Lama Mulki Suzanne Krishfield Fabio Malavasi Joon Yoon Shannan J. Ho Sui Vasileios C. Kyttaris George C. Tsokos The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections Cell Reports |
| title | The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
| title_full | The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
| title_fullStr | The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
| title_full_unstemmed | The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
| title_short | The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
| title_sort | cd38 nad sirtuin1 ezh2 axis mitigates cytotoxic cd8 t cell function and identifies patients with sle prone to infections |
| url | http://www.sciencedirect.com/science/article/pii/S221112471931664X |
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