A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism of Regulatory and Conventional CD4 T Cells.
A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism of Regulatory and Conventional CD4 T Cells.
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DOI：
10.4049/jimmunol.1600696
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发表时间：
2016-08-15
期刊：
影响因子：
--
通讯作者：
Raimondi G
中科院分区：
文献类型：
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作者：
Chen LC;Nicholson YT;Rosborough BR;Thomson AW;Raimondi G
维生素A代谢物全反式维甲酸（ATRA）通过上调整合素α4β7和趋化因子受体CCR9在活化的CD4+常规T细胞（Tconv）中诱导肠道归巢表型。我们报道，与小鼠Tconv相比，只有约50%的调节性T细胞（Treg）在受到生理水平的ATRA刺激时上调CCR9，尽管Tconv和Treg表达相似水平的视黄酸受体（RAR）。由此产生的双峰CCR9表达与它们的增殖程度、Foxp3表达水平或与循环Treg池中自然产生的Treg （nTreg）或诱导的Treg （iTreg）的关系无关。此外，我们发现Treg暴露于雷帕霉素（rapamycin, mTOR）抑制剂雷帕霉素的机制靶点可抑制CCR9和α4β7的上调，而Tconv的作用并不明显。这表明在Treg中，atra诱导的CCR9和α4β7的上调依赖于mTOR信号通路的激活。mTOR的参与与Akt活性无关，因为特异性抑制Akt、丙酮酸脱氢酶激酶-1或其下游靶糖原合成酶激酶-3并不能阻止CCR9的表达。此外，Rictor （mTOR complex [C] 2）缺陷Treg表达CCR9的能力不变，而Raptor （mTORC1）缺陷Treg无法上调CCR9，提示mTORC1的选择性参与。这些发现揭示了Treg和Tconv中ATRA信号和趋化因子受体诱导之间的新差异，并提供了一个框架，通过该框架，Treg和Tconv的迁移行为可能被调节为治疗目的的差异。
The vitamin A metabolite all-trans retinoic acid (ATRA) induces a gut-homing phenotype in activated CD4+ conventional T cells (Tconv) by upregulating the integrin α4β7 and the chemokine receptor CCR9. We report that, in contrast to mouse Tconv, only about 50% of regulatory T cells (Treg) upregulate CCR9 when stimulated by physiological levels of ATRA, even though Tconv and Treg express similar levels of the retinoic acid receptor (RAR). The resulting bimodal CCR9 expression is not associated with differences in the extent of their proliferation, level of Foxp3 expression, or affiliation with naturally-occurring Treg (nTreg) or induced Treg (iTreg) in the circulating Treg pool. Furthermore, we find that exposure of Treg to the mechanistic target of rapamycin (mTOR) inhibitor rapamycin suppresses upregulation of both CCR9 and α4β7, an effect that is not evident with Tconv. This suggests that in Treg, ATRA-induced upregulation of CCR9 and α4β7 is dependent on activation of an mTOR signaling pathway. The involvement of mTOR is independent of Akt activity, since specific inhibition of Akt, pyruvate dehydrogenase kinase-1, or its downstream target glycogen synthase kinase-3, did not prevent CCR9 expression. Additionally, Rictor (mTOR complex [C] 2)-deficient Treg showed unaltered ability to express CCR9, whereas Raptor (mTORC1)-deficient Treg were unable to upregulate CCR9, suggesting the selective participation of mTORC1. These findings reveal a novel difference between ATRA signaling and chemokine receptor induction in Treg versus Tconv and provide a framework via which the migratory behavior of Treg versus Tconv might be regulated differentially for therapeutic purposes.