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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
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.
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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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