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The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections
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 CD8CD38(high) T cell subset i...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577012/ https://www.ncbi.nlm.nih.gov/pubmed/31914379 http://dx.doi.org/10.1016/j.celrep.2019.12.014 |
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author | Katsuyama, Eri Suarez-Fueyo, Abel Bradley, Sean J. Mizui, Masayuki Marin, Ana V. Mulki, Lama Krishfield, Suzanne Malavasi, Fabio Yoon, Joon Ho Sui, Shannan J. Kyttaris, Vasileios C. Tsokos, George C. |
author_facet | Katsuyama, Eri Suarez-Fueyo, Abel Bradley, Sean J. Mizui, Masayuki Marin, Ana V. Mulki, Lama Krishfield, Suzanne Malavasi, Fabio Yoon, Joon Ho Sui, Shannan J. Kyttaris, Vasileios C. Tsokos, George C. |
author_sort | Katsuyama, Eri |
collection | PubMed |
description | 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 CD8CD38(high) T cell subset in a sub-group of patients with increased rates of infections. CD8CD38(high) 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 CD8CD38(high) 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. |
format | Online Article Text |
id | pubmed-7577012 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-75770122020-10-21 The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections Katsuyama, Eri Suarez-Fueyo, Abel Bradley, Sean J. Mizui, Masayuki Marin, Ana V. Mulki, Lama Krishfield, Suzanne Malavasi, Fabio Yoon, Joon Ho Sui, Shannan J. Kyttaris, Vasileios C. Tsokos, George C. Cell Rep Article 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 CD8CD38(high) T cell subset in a sub-group of patients with increased rates of infections. CD8CD38(high) 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 CD8CD38(high) 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. 2020-01-07 /pmc/articles/PMC7577012/ /pubmed/31914379 http://dx.doi.org/10.1016/j.celrep.2019.12.014 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Katsuyama, Eri Suarez-Fueyo, Abel Bradley, Sean J. Mizui, Masayuki Marin, Ana V. Mulki, Lama Krishfield, Suzanne Malavasi, Fabio Yoon, Joon Ho Sui, Shannan J. Kyttaris, Vasileios C. Tsokos, George C. The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections |
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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577012/ https://www.ncbi.nlm.nih.gov/pubmed/31914379 http://dx.doi.org/10.1016/j.celrep.2019.12.014 |
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