miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis.
miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis.
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DOI：
10.4049/jimmunol.1103171
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Whitacre CC
中科院分区：
文献类型：
--
作者：
Smith KM;Guerau-de-Arellano M;Costinean S;Williams JL;Bottoni A;Mavrikis Cox G;Satoskar AR;Croce CM;Racke MK;Lovett-Racke AE;Whitacre CC
辅助性T细胞的编程和功能受到复杂的生物网络的严格调控，以防止过度的炎症反应和自身免疫性疾病。miRNAs在这一过程中的重要性通过缺乏miRNAs的Dicer缺陷型T细胞的优先Th 1极化来强调。使用基因敲除，我们证明来源于miR-29 ab 1基因组簇的内源性miR-29的缺失导致不受限制的T-bet表达和IFN-γ产生。miR-29 b通过与3′ UTR的直接相互作用调节T-bet和IFN-γ，IFN-γ本身增强miR-29 b的表达，建立了一个新的调节反馈环。miR-29 b在多发性硬化（MS）患者的记忆性CD 4 + T细胞中增加，这可能反映了慢性Th 1炎症。然而，在MS患者中，miR-29 b水平在T细胞活化后显著降低，表明该反馈回路在MS患者中失调，并可能导致慢性炎症。因此，miR-29作为一种新的Th 1分化调节因子，增加了对维持保护性免疫和自身免疫之间平衡的T细胞内在调节机制的理解。
T-helper cell programming and function is tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease. The importance of miRNAs in this process is highlighted by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. Using genetic knockouts, we demonstrate that loss of endogenous miR-29, derived from the miR-29ab1 genomic cluster, results in unrestrained T-bet expression and IFN-γ production. miR-29b regulates T-bet and IFN-γ via a direct interaction with the 3′UTRs, and IFN-γ itself enhances miR-29b expression, establishing a novel regulatory feedback loop. miR-29b is increased in memory CD4+ T cells from multiple sclerosis (MS) patients, which may reflect chronic Th1 inflammation. However, miR-29b levels decrease significantly upon T cell activation in MS patients, suggesting that this feedback loop is dysregulated in MS patients and may contribute to chronic inflammation. miR-29 thus serves as a novel regulator of Th1 differentiation, adding to the understanding of T cell-intrinsic regulatory mechanisms that maintain a balance between protective immunity and autoimmunity.
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DOI：
10.1084/jem.20061692
发表时间：
2006-10-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cobb BS;Hertweck A;Smith J;O'Connor E;Graf D;Cook T;Smale ST;Sakaguchi S;Livesey FJ;Fisher AG;Merkenschlager M
通讯作者：
Merkenschlager M
影响因子：
3.3
作者：
De Santis, Giuseppe;Ferracin, Manuela;Granieri, Enrico
通讯作者：
Granieri, Enrico
影响因子：
3.2
作者：
Ceolotto, Giulio;Papparella, Italia;Semplicini, Andrea
通讯作者：
Semplicini, Andrea
影响因子：
56.9
作者：
ALLEGRETTA, M;NICKLAS, JA;ALBERTINI, RJ
通讯作者：
ALBERTINI, RJ
影响因子：
30.8
作者：
Chang, Tsung-Cheng;Yu, Duonan;Mendell, Joshua T.
通讯作者：
Mendell, Joshua T.