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

作者：Eri Katsuyama, Abel Suárez‐Fueyo, Sean J. Bradley, Masayuki Mizui, Ana V. Marín, Lama Mulki, Suzanne Krishfield, Fabio Malavasi, Joon Yoon, Shannan J. Ho Sui, Vasileios C. Kyttaris, George C. Tsokos · 发表于：Cell Reports · 年份：2020 · DOI：10.1016/j.celrep.2019.12.014 · 被引用次数：161 · 研究领域：Calcium signaling and nucleotide metabolism、Cytomegalovirus and herpesvirus research、Adenosine and Purinergic Signaling

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 subgroup 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.