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Epstein-Barr virus (EBV) infection is usually asymptomatic and latency occurs in B cells. We studied three patients with NK cell chronic active EBV (CAEBV) disease and EBV hepatitis. All patients had an increased number of NK cells, and high levels of EBV in the blood, with EBV predominantly in NK cells; two patients who were tested had an NK cell receptor repertoire consistent with immature cells. All three patients had increased phosphorylation of Akt and ribosomal protein S6 in NK cells and a marked increase in STAT1; two of the patients had increased phosphorylation of STAT1 in their T cells, NK cells, and monocytes. Treatment of one of these patients with sirolimus, an mTOR inhibitor, reduced phosphorylation of S6 in the patient’s T and B cells, but not in her NK cells and did not reduce the level of NK cells or EBV DNA in the peripheral blood. The increased STAT1 activity observed in two of the patients was reduced to normal when the cells were treated with JAK inhibitors in vitro. Unlike other patients with STAT1 gain-of-function (GOF) mutations, no mutations were identified in STAT1 or STAT1 regulatory proteins. Patients with T or B cell CAEBV also had increased phosphorylation of Akt and S6, but not STAT1. In summary, the increase in Akt and S6 phosphorylation, and the increase in STAT1 protein, as well as immature NK cells in our NK cell patients describe a novel phenotype in NK cell CAEBV disease.

Regulators of G-protein Signaling (RGS) proteins negatively regulate GPCRs by accelerating the GTPase activity of Gα. In recent years, non-GPCR-related functions have also been described for these proteins. We found previously that RGS13 was enriched in mast cells and inhibited anaphylaxis in mice by suppressing IgE-mediated mast cell degranulation. We therefore examined the transcriptional regulation of RGS13 in mast cells. We confirmed the transcriptional start site (TSS) by 5’ RACE in cDNA from the human mast cell line LAD2 and demonstrated promoter activity in a ~ 1 kb element upstream of exon 1 using luciferase reporter assays. We also identified 2 potential p53 response elements (RE) in the region 2 kb upstream of the TSS by bioinformatic analysis. Overexpression and shRNA-mediated knockdown of endogenous p53 in LAD2 cells revealed an inverse relationship between p53 levels and RGS13 expression. Endogenous p53 in these cells bound exclusively to oligonucleotides containing the p53 RE most upstream of the TSS. Cells expressing double-stranded oligonucleotides containing this site or a p53 consensus site had enhanced promoter activity. These studies indicate that p53 suppresses RGS13 transcription in mast cells. Thus, upregulation of p53 activity in mast cells exposed to stress could reduce the threshold for degranulation as a result of decreased RGS13 expression.