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

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

Functionally-separate intracellular ca2+ stores in smooth muscle

In smooth muscle, release via the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3R) and ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) controls oscillatory and steady-state cytosolic Ca2+ concentrations ([Ca2+]c). The interplay between the two receptors, itself determined by their organization on the SR, establishes the time course and spatial arrangement of the Ca2+ signal. Whether or not the receptors are co-localized or distanced from each other on the same store or whether they exist on separate stores will significantly affect the Ca2+ signal produced by the SR. To date these matters remain unresolved. The functional arrangement of the RyR and Ins(1,4,5)P3R on the SR has now been examined in isolated single voltage-clamped colonic myocytes. Depletion of the ryanodine-sensitive store, by repeated application of caffeine, in the presence of ryanodine, abolished the response to Ins(1,4,5)P3, suggesting that Ins(1,4,5)P3R and RyR share a common Ca2+store. Ca2+ release from the Ins(1,4,5)P3R did not activate Ca2+-induced Ca2+ release at the RyR. Depletion of the Ins(1,4,5)P3-sensitive store, by the removal of external Ca2+, on the other hand, caused only a small decrease (∼26%) in caffeine-evoked Ca2+transients, suggesting that not all RyR exist on the common store shared with Ins(1,4,5)P3R. Dependence of the stores on external Ca2+ for replenishment also differed; removal of external Ca2+ depleted the Ins(1,4,5)P3-sensitive store but caused only a slight reduction in caffeine-evoked transients mediated at RyR. Different mechanisms are presumably responsible for the refilling of each store. Refilling of both Ins(1,4,5)P3-sensitive and caffeine-sensitive Ca2+ stores was inhibited by each of the SR Ca2+ ATPase inhibitors thapsigargin and cyclopiazonic acid. These results may be explained by the existence of two functionally distinct Ca2+ stores; the first expressing only RyR and refilled from [Ca2+]c, the second expressing both Ins(1,4,5)P3R and RyR and dependent upon external Ca2+ for refilling