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A3.22 Upregulated microRNA-182 Expression is Associated with Enhanced Conventional CD4+ T Cell Proliferation in SLE
  1. Tobias Alexander1,2,
  2. Claudia Haftmann2,
  3. Lars Templin2,
  4. Jens Humrich1,2,
  5. Gerd-Rüdiger Burmester1,
  6. Andreas Radbruch2,
  7. Falk Hiepe1,2,
  8. Mir-Farzin Mashreghi2
  1. 1Medical Department, Division of Rheumatology and Clinical Immunology, Charité – University Medicine Berlin, Germany
  2. 2German Rheumatism Research Center (DRFZ), Berlin, Germany

Abstract

Background Recent reports have shown dysregulated microRNAs (miRNAs) in murine models of lupus, among them increased expression of miRNA-182, which has been demonstrated to target the transcription factor FOXO1 in activated murine CD4+ T cells. The loss of FOXO1 activity in T cells is associated with spontaneous T cell activation, clonal expansion and autoantibody production, all of which are present in systemic lupus erythematosus (SLE).

Methods Expression levels of microRNA-182 (miR-182) and FOXO1 were analysed with RT-PCR in freshly isolated and magnetic 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 CCR7, CD45RA, 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 (R&D systems). The Wilcoxon signed-rank test was used for statistical analysis.

Results MiRNA-182 was significantly upregulated in CD4+ T cells from SLE patients compared to HC (median relative expression 8.89 × 10E-7 versus 3.96 × 10E-7, p = 0.008) while FOXO1 mRNA levels were decreased, yet without reaching statistical significance. Analysis of Ki-67 expression revealed an increased percentage of proliferating CD4+ T cells in SLE (5.23% versus 2.21%, p = 0.006), which was more prominent in Foxp3- conventional T cells (Tcons) than in Foxp3+ regulatory T cells (Tregs). Overall, CD4+ T cellular proliferation in SLE was associated with increased frequencies of CD45RA CCR7 effector memory T cells and enhanced basal pSTAT5 levels (median MFI 503.5 versus 399.0, p = 0.010), suggesting a recent stimulation with common gamma chain(γc)-signalling cytokines. In this regard, Tcons from SLE samples displayed decreased expression levels for the FOXO1 target gene CD127 (MFI 2021 versus 2553, p = 0.049) and serum IL-7 levels were significantly higher in SLE when compared to HC (17.0 pg/ml versus 10.2 pg/ml, p = 0.001).

Conclusions MiR-182 expression has been shown to be directly dependent on STAT5 activation and to promote the clonal expansion of murine activated CD4+ T cells. Our data suggest that enhanced IL7R/STAT5 signalling presumably mediates the induction of miR182 expression, which in turn promotes the proliferation of Tcons in SLE. The relative contribution of IL7R/miR-182/FOXO1 axis on the enhanced proliferative capacity of SLE Tcons remains elusive and merit further investigation. Collectively, our data provide new insights in the pathophysiology of T cell hyper- activity in SLE and identifies miR-182 as a candidate target for future therapeutic approaches.

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