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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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Treg-specific miR-17∼92a deficiency results in immunologic abnormalities.Littermate Mir17∼92afl/fl Foxp3CreYFP/CreYFP(Y) (KO) and Mir17∼92afl/+ Foxp3KI/KI(Y) control (WT) pairs (n = 9) were analyzed at ∼15 weeks of age. T cell populations in the spleen and lymph node were stained for memory phenotype markers. Shown are (A) CD4+ T cells with an effector memory (CD44hiCD62Llo) phenotype, and (B) CD8+ T cells with an activated/central memory (CD44hiCD62Lhi) phenotype. Paired t tests were performed for statistical comparisons. (C) An accumulation of large numbers of granulocytic (CD11b+Ly-6G+) cells can also be observed in the spleens of older KO mice.
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pone-0088997-g005: Treg-specific miR-17∼92a deficiency results in immunologic abnormalities.Littermate Mir17∼92afl/fl Foxp3CreYFP/CreYFP(Y) (KO) and Mir17∼92afl/+ Foxp3KI/KI(Y) control (WT) pairs (n = 9) were analyzed at ∼15 weeks of age. T cell populations in the spleen and lymph node were stained for memory phenotype markers. Shown are (A) CD4+ T cells with an effector memory (CD44hiCD62Llo) phenotype, and (B) CD8+ T cells with an activated/central memory (CD44hiCD62Lhi) phenotype. Paired t tests were performed for statistical comparisons. (C) An accumulation of large numbers of granulocytic (CD11b+Ly-6G+) cells can also be observed in the spleens of older KO mice.

Mentions: Although the abnormalities caused by miR-17∼92a deficiency in Tregs were mild compared to the dramatic phenotypes caused by ablating the entire miRNA pathway, there may still be consequences of these relatively minor abnormalities. Indeed, we found that in older mice, the lack of miR-17∼92a expressing Tregs led to increases in CD4+ T cells with an effector memory CD44hiCD62Llo phenotype (Figure 5A), and CD8+ T cells with an activated/central memory CD44hiCD62Lhi phenotype (Figure 5B). Furthermore, we noticed a substantial accumulation of CD11b+Ly-6G+ granulocytic cells in the spleen of some older mice (Figure 5C). Thus, the expression of miR-17∼92a miRNAs in Tregs is necessary for their fitness and for general immunologic homeostasis.


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)

Treg-specific miR-17∼92a deficiency results in immunologic abnormalities.Littermate Mir17∼92afl/fl Foxp3CreYFP/CreYFP(Y) (KO) and Mir17∼92afl/+ Foxp3KI/KI(Y) control (WT) pairs (n = 9) were analyzed at ∼15 weeks of age. T cell populations in the spleen and lymph node were stained for memory phenotype markers. Shown are (A) CD4+ T cells with an effector memory (CD44hiCD62Llo) phenotype, and (B) CD8+ T cells with an activated/central memory (CD44hiCD62Lhi) phenotype. Paired t tests were performed for statistical comparisons. (C) An accumulation of large numbers of granulocytic (CD11b+Ly-6G+) cells can also be observed in the spleens of older KO mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3921252&req=5

pone-0088997-g005: Treg-specific miR-17∼92a deficiency results in immunologic abnormalities.Littermate Mir17∼92afl/fl Foxp3CreYFP/CreYFP(Y) (KO) and Mir17∼92afl/+ Foxp3KI/KI(Y) control (WT) pairs (n = 9) were analyzed at ∼15 weeks of age. T cell populations in the spleen and lymph node were stained for memory phenotype markers. Shown are (A) CD4+ T cells with an effector memory (CD44hiCD62Llo) phenotype, and (B) CD8+ T cells with an activated/central memory (CD44hiCD62Lhi) phenotype. Paired t tests were performed for statistical comparisons. (C) An accumulation of large numbers of granulocytic (CD11b+Ly-6G+) cells can also be observed in the spleens of older KO mice.
Mentions: Although the abnormalities caused by miR-17∼92a deficiency in Tregs were mild compared to the dramatic phenotypes caused by ablating the entire miRNA pathway, there may still be consequences of these relatively minor abnormalities. Indeed, we found that in older mice, the lack of miR-17∼92a expressing Tregs led to increases in CD4+ T cells with an effector memory CD44hiCD62Llo phenotype (Figure 5A), and CD8+ T cells with an activated/central memory CD44hiCD62Lhi phenotype (Figure 5B). Furthermore, we noticed a substantial accumulation of CD11b+Ly-6G+ granulocytic cells in the spleen of some older mice (Figure 5C). Thus, the expression of miR-17∼92a miRNAs in Tregs is necessary for their fitness and for general immunologic homeostasis.

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