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

Cell Rep. 2020 Jan 7;30(1):112-123.e4. 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.

Keywords: CD38; CD8 T cell; EZH2; Sirtuin1; cytotoxicity; infection; nicotinamide adenine dinucleotide; patients; systemic lupus erythematosus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism*
  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Female
  • Humans
  • Infections / immunology*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / microbiology
  • Male
  • NAD / metabolism*
  • Sirtuin 1 / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcription Factors / metabolism


  • Transcription Factors
  • NAD
  • Enhancer of Zeste Homolog 2 Protein
  • ADP-ribosyl Cyclase 1
  • Sirtuin 1