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02.34 Enhanced conventional cd4+ t cell proliferation in sle is associated with up-regulation of microrna-182 and increased il-7 receptor signalling
  1. Tobias Alexander1,2,
  2. Claudia Haftmann2,
  3. René Riedel2,
  4. Lars Templin2,
  5. Jens Humrich1,2,
  6. Gerd-Rüdiger Burmester1,
  7. Andreas Radbruch2,
  8. Falk Hiepe1,2,
  9. Mir-Farzin Mashreghi2
  1. 1Medical Department, Division of Rheumatology and Clinical Immunology, Charité – University Medicine Berlin, Germany
  2. 2German Rheumatism Research Centre (DRFZ), Berlin, Germany

Abstract

Background Recent reports have shown dysregulated microRNAs (miRNAs) in murine models of lupus, among them increased expression of microRNA-182 (miRNA-182), which has been demonstrated to target the transcription factor FOXO1 in activated murine CD4+ T cells, leading to spontaneous T cell activation and clonal expansion. Here we aimed to investigate the expression of miR-182 and FOXO1 in T cells from human SLE patients.

Methods Expression levels of miR-182 were analysed with RT-PCR in purified peripheral blood CD4+ T cells from 9 patients with SLE and age/sex-matched healthy controls (HC). Multicolor flow cytometry was performed to analyse CD4+ T cell expression for FOXO1, Ki-67, Foxp3, the interleukin-7 receptor-α (CD127) and phosphorylated STAT-5a (pSTAT5). Analysis of serum IL-7 levels was performed with ELISA in 27 SLE patients and HC. Induction of miR-182 was assessed in vitro after polyclonal T cell stimulation in the presence of IL-7, and inhibition of T cell proliferation investigated using mir-182 antagomirs.

Results MiRNA-182 was significantly upregulated in CD4+ T cells from SLE patients compared to HC, while the FOXO1 expression was significantly decreased. The percentage of proliferating Ki-67+ conventional Foxp3- CD4+ T cells TCON was significantly higher in SLE compared to HC (3.85% vs. 1.58%, p<0.001) and their basal pSTAT5 levels significantly enhanced, suggesting a recent stimulation with common gamma chain(γc)-signalling cytokines. SLE TCON displayed decreased expression levels for the FOXO1 target gene CD127 (MFI 2021 vs. 2553, p=0.049) and serum IL-7 levels were significantly higher in SLE compared to HC (17.0 pg/ml vs. 10.2 pg/ml, p=0.001). In vitro, miR-182 could be induced by IL-7, and specific inhibition of miR-182 inhibited T cell proliferation and survival.

Conclusion Our data suggest that enhanced IL7R/STAT5 signalling mediates the induction of miR182 expression, which promotes the proliferation of conventional Foxp3- T cells SLE. Collectively, our data provide new insights in the pathophysiology of T cell hyperactivity in SLE and identifies miR-182 as a candidate target for future therapeutic approaches.

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