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The miR-17 ∼ 92a cluster of microRNAs is required for the fitness of Foxp3+ regulatory T cells.

Skinner JP, Keown AA, Chong MM - PLoS ONE (2014)

Bottom Line: In this study, we identified members of the miR-17 ∼ 92a cluster of microRNAs to be enriched in regulatory T cells.This led to a loss of Foxp3(+) cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations.Thus, miR-17 ∼ 92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.

View Article: PubMed Central - PubMed

Affiliation: St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

ABSTRACT
By genetic inactivation of key microRNA biogenesis enzymes, we and others have previously demonstrated the critical requirement of the microRNA pathway for the differentiation and function of Foxp3(+) regulatory T cells. In this study, we identified members of the miR-17 ∼ 92a cluster of microRNAs to be enriched in regulatory T cells. To investigate the function of this microRNA cluster, we deleted the gene specifically in Foxp3(+) cells in mice. We found that miR-17 ∼ 92a is required for the fitness of regulatory T cells, and deficiency impacted at the level of apoptosis and proliferation of these cells. This led to a loss of Foxp3(+) cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations. Thus, miR-17 ∼ 92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.

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Related in: MedlinePlus

The miR-17∼92a cluster of miRNAs are enriched in Tregs.(A) Relative expression of the miR-17∼92a miRNAs species determined by Illumina high throughput sequencing. Shown is expression in sorted CD4+CD25+ Tregs compared to CD4+CD25− conventional T cells, CD8+ T cells, bone marrow Lin−Sca+Kit+ stem cells, and embryonic fibroblasts (MEF) from C57BL/6 mice. The arrows indicate those species enriched in Tregs. (B) Quantitation of two miR-17∼92a miRNAs by Taqman-based RT-PCR. All miRNA levels were normalized to U6 snRNA. The indicated populations were sorted from Foxp3IRES-GFP mice, in which Foxp3 expression was identified by GFP fluorescence.
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pone-0088997-g001: The miR-17∼92a cluster of miRNAs are enriched in Tregs.(A) Relative expression of the miR-17∼92a miRNAs species determined by Illumina high throughput sequencing. Shown is expression in sorted CD4+CD25+ Tregs compared to CD4+CD25− conventional T cells, CD8+ T cells, bone marrow Lin−Sca+Kit+ stem cells, and embryonic fibroblasts (MEF) from C57BL/6 mice. The arrows indicate those species enriched in Tregs. (B) Quantitation of two miR-17∼92a miRNAs by Taqman-based RT-PCR. All miRNA levels were normalized to U6 snRNA. The indicated populations were sorted from Foxp3IRES-GFP mice, in which Foxp3 expression was identified by GFP fluorescence.

Mentions: By targeted mutagenesis of key miRNA pathway components in mice, we and others previously demonstrated the critical requirement of miRNAs for the Foxp3+ Treg lineage [20]–[22]. In order to identify specific miRNAs that might be important in Tregs, we analyzed the miRNA profiles of T cell lineages that we previously generated by Illumina high throughput sequencing [23], [32]. This analysis revealed numerous miRNA species from the miR-17∼92a cluster of miRNAs to be enriched in Tregs compared to other T cell populations, bone marrow stem cells and fibroblasts (Figure 1A). The enrichment of miR-17 and miR-92a were also confirmed by Taqman-based RT-PCR assay (Figure 1B).


The miR-17 ∼ 92a cluster of microRNAs is required for the fitness of Foxp3+ regulatory T cells.

Skinner JP, Keown AA, Chong MM - PLoS ONE (2014)

The miR-17∼92a cluster of miRNAs are enriched in Tregs.(A) Relative expression of the miR-17∼92a miRNAs species determined by Illumina high throughput sequencing. Shown is expression in sorted CD4+CD25+ Tregs compared to CD4+CD25− conventional T cells, CD8+ T cells, bone marrow Lin−Sca+Kit+ stem cells, and embryonic fibroblasts (MEF) from C57BL/6 mice. The arrows indicate those species enriched in Tregs. (B) Quantitation of two miR-17∼92a miRNAs by Taqman-based RT-PCR. All miRNA levels were normalized to U6 snRNA. The indicated populations were sorted from Foxp3IRES-GFP mice, in which Foxp3 expression was identified by GFP fluorescence.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921252&req=5

pone-0088997-g001: The miR-17∼92a cluster of miRNAs are enriched in Tregs.(A) Relative expression of the miR-17∼92a miRNAs species determined by Illumina high throughput sequencing. Shown is expression in sorted CD4+CD25+ Tregs compared to CD4+CD25− conventional T cells, CD8+ T cells, bone marrow Lin−Sca+Kit+ stem cells, and embryonic fibroblasts (MEF) from C57BL/6 mice. The arrows indicate those species enriched in Tregs. (B) Quantitation of two miR-17∼92a miRNAs by Taqman-based RT-PCR. All miRNA levels were normalized to U6 snRNA. The indicated populations were sorted from Foxp3IRES-GFP mice, in which Foxp3 expression was identified by GFP fluorescence.
Mentions: By targeted mutagenesis of key miRNA pathway components in mice, we and others previously demonstrated the critical requirement of miRNAs for the Foxp3+ Treg lineage [20]–[22]. In order to identify specific miRNAs that might be important in Tregs, we analyzed the miRNA profiles of T cell lineages that we previously generated by Illumina high throughput sequencing [23], [32]. This analysis revealed numerous miRNA species from the miR-17∼92a cluster of miRNAs to be enriched in Tregs compared to other T cell populations, bone marrow stem cells and fibroblasts (Figure 1A). The enrichment of miR-17 and miR-92a were also confirmed by Taqman-based RT-PCR assay (Figure 1B).

Bottom Line: In this study, we identified members of the miR-17 ∼ 92a cluster of microRNAs to be enriched in regulatory T cells.This led to a loss of Foxp3(+) cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations.Thus, miR-17 ∼ 92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.

View Article: PubMed Central - PubMed

Affiliation: St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

ABSTRACT
By genetic inactivation of key microRNA biogenesis enzymes, we and others have previously demonstrated the critical requirement of the microRNA pathway for the differentiation and function of Foxp3(+) regulatory T cells. In this study, we identified members of the miR-17 ∼ 92a cluster of microRNAs to be enriched in regulatory T cells. To investigate the function of this microRNA cluster, we deleted the gene specifically in Foxp3(+) cells in mice. We found that miR-17 ∼ 92a is required for the fitness of regulatory T cells, and deficiency impacted at the level of apoptosis and proliferation of these cells. This led to a loss of Foxp3(+) cells over time, particularly in competitive settings, and culminated in a range of immunologic perturbations. Thus, miR-17 ∼ 92a-target interactions are part of the essential microRNA networks that safeguard the regulatory T cell lineage.

Show MeSH
Related in: MedlinePlus