Cell Reports
Volume 30, Issue 1, 7 January 2020, Pages 112-123.e4
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Article
The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

https://doi.org/10.1016/j.celrep.2019.12.014Get rights and content
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Highlights

  • Expanded CD8CD38high T cells in SLE patients identify patients with infections

  • CD8CD38high T cells express decreased amounts of cytotoxic molecules

  • CD38 decreases NAD+ and SIRT1 activity and releases the activity of EZH2

  • Inhibition of EZH2 restores the degranulation capacity of CD8CD38high T cells

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.

Keywords

systemic lupus erythematosus
patients
CD8 T cell
CD38
cytotoxicity
infection
nicotinamide adenine dinucleotide
Sirtuin1
EZH2

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