Induced miR‐99a expression represses Mtor cooperatively with miR‐150 to promote regulatory T‐cell differentiation
Induced miR‐99a expression represses Mtor cooperatively with miR‐150 to promote regulatory T‐cell differentiation
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DOI：
10.15252/embj.201489589
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发表时间：
2015-05
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通讯作者：
Sebastian C Warth;Kai P Hoefig;Anian Hiekel;S. Schallenberg;K. Jovanovic;L. Klein;Karsten Kretschmer;K. Ansel;V. Heissmeyer
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作者：
Sebastian C Warth;Kai P Hoefig;Anian Hiekel;S. Schallenberg;K. Jovanovic;L. Klein;Karsten Kretschmer;K. Ansel;V. Heissmeyer
调节性T(Treg)细胞的外周诱导提供了必要的保护，使其免受不适当的免疫反应。缺乏内源性miRNAs的CD4+T细胞分化为Treg细胞的能力受损，但相关的miRNAs尚不清楚。我们用T细胞表达的miRNAs在经历Treg分化的幼鼠CD4+T细胞中进行了过表达筛选。在130个候选者中，筛选出29个miRNAs为阴性，10个miRNAs为阳性。Th17相互分化试验揭示了miR-100、miR-99a和miR-10b的特定功能，因为所有这些都促进Treg并抑制Th17程序，而不影响细胞的存活、增殖和激活。MiR-99a与miR-150协同抑制Th17促进因子mTOR的表达。在Treg细胞诱导剂维甲酸的作用下，miR-99a相对较低的表达被强烈上调，而高表达的miR-150仅在miR-99a存在的情况下抑制mTOR。我们的数据表明，Treg细胞的诱导分化受miRNA网络的调控，该网络涉及组成性表达的miRNAs和可诱导的miRNAs的合作。
Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4+ T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T‐cell‐expressed miRNAs in naive mouse CD4+ T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR‐100, miR‐99a and miR‐10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR‐99a cooperated with miR‐150 to repress the expression of the Th17‐promoting factor mTOR. The comparably low expression of miR‐99a was strongly increased by the Treg cell inducer “retinoic acid”, and the abundantly expressed miR‐150 could only repress Mtor in the presence of miR‐99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs.