miR-155, a Modulator of FOXO3a Protein Expression, Is Underexpressed and Cannot Be Upregulated by Stimulation of HOZOT, a Line of Multifunctional Treg

Abstract

MicroRNAs (miRNAs) play important roles in regulating post-transcriptional gene repression in a variety of immunological processes. In particular, much attention has been focused on their roles in regulatory T (Treg) cells which are crucial for maintaining peripheral tolerance and controlling T cell responses. Recently, we established a novel type of human Treg cell line, termed HOZOT, multifunctional cells exhibiting a CD4+CD8+ phenotype. In this study, we performed miRNA profiling to identify signature miRNAs of HOZOT, and therein identified miR-155. Although miR-155 has also been characterized as a signature miRNA for FOXP3+ natural Treg (nTreg) cells, it was expressed quite differently in HOZOT cells. Under both stimulatory and non-stimulatory conditions, miR-155 expression remained at low levels in HOZOT, while its expression in nTreg and conventional T cells remarkably increased after stimulation. We next searched candidate target genes of miR-155 through bioinformatics, and identified FOXO3a, a negative regulator of Akt signaling, as a miR-155 target gene. Further studies by gain- and loss-of-function experiments supported a role for miR-155 in the regulation of FOXO3a protein expression in conventional T and HOZOT cells.

Micro-RNA 155 Is Required for Optimal CD8+ T Cell Responses to Acute Viral and Intracellular Bacterial Challenges

“…One signaling pathway that is targeted at multiple levels by mir-155 (15,25,26), and could reasonably account for the defect observed, is the PI3K/Akt signaling cascade. We isolated CD8 + T cells from WT and 155KO mice and stimulated them with anti-CD3 for 30 min in vitro.…”

“…Mice lacking mir-155 have a multitude of immune defects, including impaired germinal center formation (11,12), CD4 + T cell function, regulatory T (Treg) cell development, and homeostatic expansion (13)(14)(15). The defects observed in the CD4 + T cell population include a Th2-skewing bias (11,12,16) as well as an inability to produce functional Th17 cells leading to resistance to the induction of experimental autoimmune encephalomyelitis (17,18) and experimental rheumatoid arthritis (9,19).…”

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

“…Recent evidence has suggested that miR-155 can regulate the development of Tregs (35,36). Therefore, we investigated whether APCs including DCs, macrophages, and B cells were critical for the proliferation of Tregs in vivo (35, 37-39) and were involved in the development of ALI (27,40).…”

Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

“…142 As Foxp3 is proposed to upregulate miR-155 expression by inducing its resident gene, and FOXO3a is a positive regulator of Foxp3 expression, this could provide a negative feedback of Foxp3 expression through miRNAs. Other studies have found that miR-142-3p can regulate adenyl cyclase 9 mRNA and the subsequent production of cAMP in Treg cells.…”