miR-155 Inhibition Sensitizes CD4+ Th Cells for TREG Mediated Suppression

Abstract

BackgroundIn humans and mice naturally occurring CD4+CD25+ regulatory T cells (nTregs) are a thymus-derived subset of T cells, crucial for the maintenance of peripheral tolerance by controlling not only potentially autoreactive T cells but virtually all cells of the adaptive and innate immune system. Recent work using Dicer-deficient mice irrevocably demonstrated the importance of miRNAs for nTreg cell-mediated tolerance.Principal FindingsDNA-Microarray analyses of human as well as murine conventional CD4+ Th cells and nTregs revealed a strong up-regulation of mature miR-155 (microRNA-155) upon activation in both populations. Studying miR-155 expression in FoxP3-deficient scurfy mice and performing FoxP3 ChIP-Seq experiments using activated human T lymphocytes, we show that the expression and maturation of miR-155 seem to be not necessarily regulated by FoxP3. In order to address the functional relevance of elevated miR-155 levels, we transfected miR-155 inhibitors or mature miR-155 RNAs into freshly-isolated human and mouse primary CD4+ Th cells and nTregs and investigated the resulting phenotype in nTreg suppression assays. Whereas miR-155 inhibition in conventional CD4+ Th cells strengthened nTreg cell-mediated suppression, overexpression of mature miR-155 rendered these cells unresponsive to nTreg cell-mediated suppression.ConclusionInvestigation of FoxP3 downstream targets, certainly of bound and regulated miRNAs revealed the associated function between the master regulator FoxP3 and miRNAs as regulators itself. miR-155 is shown to be crucially involved in nTreg cell mediated tolerance by regulating the susceptibility of conventional human as well as murine CD4+ Th cells to nTreg cell-mediated suppression.

Staphylococcal Enterotoxin B-Induced MicroRNA-155 Targets SOCS1 To Promote Acute Inflammatory Lung Injury

“…We observed that among the miRNAs that were dysregulated in response to SEB, miR-155 was one of the most significantly altered. It has been reported that naive CD4 ϩ T cells initially display low levels of miR-155, which is increased after the engagement of TCR by an antigen (28,29). This is consistent with our observation that miR-155 was upregulated following SEB activation.…”

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

“…[66][67][68][69] Thus, up-or downregulation of specific miRNAs in Tregs could be a new therapy method used to treat GVHD patients in clinical trials. Here, we confirm another pathway miR-146b-5p-TRAF6-NF-kB could also contribute to this area.…”

The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome

“…16 It also indirectly limits overactivation of Th1 cells by regulating Treg cell function. 13 miR-155 is upregulated in activated immune cells 17 and modulates immune responses by regulating cell differentiation (such as Th1 and Treg) and cytokine secretion (such as tumor necrosis factor-alpha) and IL-6). [18][19][20] However, we found that miR-155 was downregulated in patients with ACS, which was consistent with what Fichtlscherer et al 21 found in patients with coronary artery disease.…”