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Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells
Immunity ( IF 25.5 ) Pub Date : 2017-12-12 , DOI: 10.1016/j.immuni.2017.11.008
Katharina Essig , Desheng Hu , Joao C. Guimaraes , Dominik Alterauge , Stephanie Edelmann , Timsse Raj , Jan Kranich , Gesine Behrens , Alexander Heiseke , Stefan Floess , Juliane Klein , Andreas Maiser , Susan Marschall , Martin Hrabĕ de Angelis , Heinrich Leonhardt , Cornelis F. Calkhoven , Elfriede Noessner , Thomas Brocker , Jochen Huehn , Anne B. Krug , Mihaela Zavolan , Dirk Baumjohann , Vigo Heissmeyer

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3′ UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.



中文翻译:

Roquin抑制PI3K-mTOR信号通路来抑制T辅助细胞分化以及Treg向Tfr细胞的转化

Roquin蛋白可阻止T滤泡辅助细胞(Tfh)或T辅助细胞17(Th17)的自发性T细胞活化和异常分化。在这里,我们显示了在调节性T(Treg)细胞中缺失Roquin编码等位基因也导致了常规T细胞的活化。缺乏Roquin的Treg细胞下调CD25,获得卵泡Treg(Tfr)细胞表型,并抑制生发中心反应,但不能预防结肠炎。Roquin通过干扰miR-17〜92与Pten中重叠的顺式元素的结合来上调Pten,从而抑制PI3K-mTOR信号通路。3'UTR,并下调Foxo1特异性E3泛素连接酶Itch。Roquin的丢失增强了Akt-mTOR信号传导和蛋白质合成,而在Roquin缺陷型T细胞中抑制PI3K或mTOR纠正了Tfh和Th17增强或iTreg细胞分化降低。因此,由Roquin介导的PI3K-mTOR信号控制通过抑制常规T细胞的活化和分化以及Treg细胞的特化来防止自身免疫。

更新日期:2017-12-12
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