Foxp3-Dependent MicroRNA155 Confers Competitive Fitness to Regulatory T Cells by Targeting SOCS1 Protein

Abstract

Foxp3+ regulatory T (TR) cells limit pathogenic immune responses to self and foreign antigens. An essential role for microRNA (miRNA) in the maintenance and function of TR cells, revealed by the TR-specific Dicer ablation, raised a question as to a specific miRNA contribution. We found that Foxp3 controls the elevated miR155 expression required for maintaining TR proliferative activity and numbers under non-lymphopenic conditions. Moreover, miR155 deficiency in TR cells results in increased SOCS1 expression accompanied by impaired STAT5 activation in response to limiting amounts of IL-2. Our studies suggest Foxp3-dependent regulation of miR155 maintains competitive fitness of TR subset by targeting SOCS1, and provide an experimental support for a proposed role for miRNAs in ensuring the robustness of cellular phenotypes.

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

“…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. Two mechanisms may explain these findings.…”

“…32 Furthermore, the proportion and the absolute number of Treg cells were also smaller in miR-155-deficient mice. 19,33 In summary, these studies indicated that miR-155 is essential for the differentiation of Th cell subsets. However, different transcripts were found to be targeted by miR-155 in different Th cell subsets, and additional targets still need to be confirmed.…”

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…However, miR-141 and Treg numbers were shown to fluctuate in relapsing and remitting phases of multiple sclerosis (Naghavian et al, 2015). In addition, miRNAs, such has miR-155, which regulate normal Treg development and function (Lu et al, 2009;Gao et al, 2012;Josefowicz et al, 2012;Dooley et al, 2013;Kohlhaas et al, 2009), were not found to be altered in the naïve CD4 T cells of patients with multiple sclerosis (Guerau-de-Arellano et al, 2011). Thus, it is important to determine if these TGFb-targeting miRNAs have roles in normal Treg development that are dysregulated in patients with multiple sclerosis.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58.…”