%0 Journal Article %J Cell Rep %D 2020 %T The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections %A Katsuyama, Eri %A Suarez-Fueyo, Abel %A Bradley, Sean J %A Mizui, Masayuki %A Marin, Ana V %A Mulki, Lama %A Krishfield, Suzanne %A Malavasi, Fabio %A Yoon, Joon %A Sui, Shannan J Ho %A Kyttaris, Vasileios C %A Tsokos, George C %X 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 T cell subset in a subgroup of patients with increased rates of infections. CD8CD38 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 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. %B Cell Rep %V 30 %P 112-123.e4 %8 2020 Jan 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/31914379?dopt=Abstract %R 10.1016/j.celrep.2019.12.014