The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

• Published in: Cell reports (Cambridge) Vol. 30; no. 1; pp. 112 - 123.e4
• Main Authors: Katsuyama, Eri, Suarez-Fueyo, Abel, Bradley, Sean J., Mizui, Masayuki, Marin, Ana V., Mulki, Lama, Krishfield, Suzanne, Malavasi, Fabio, Yoon, Joon, Sui, Shannan J. Ho, Kyttaris, Vasileios C., Tsokos, George C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.01.2020; Elsevier
• Subjects: ADP-ribosyl Cyclase 1 - metabolism; Adult; CD38; CD8 T cell; CD8-Positive T-Lymphocytes - immunology; Cell Line; cytotoxicity; Enhancer of Zeste Homolog 2 Protein - metabolism; EZH2; Female; Humans; infection; Infections - immunology; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - microbiology; Male; NAD - metabolism; nicotinamide adenine dinucleotide; patients; Sirtuin 1 - metabolism; Sirtuin1; systemic lupus erythematosus; T-Lymphocytes, Cytotoxic - immunology; Transcription Factors - metabolism; nicotinamide adenine dinucleotide; systemic lupus erythematosus; infection; CD8 T cell; patients; CD38; cytotoxicity; Sirtuin1; EZH2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.12.014

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. [Display omitted] •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 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.