State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Eur J Immunol. 2014 Feb;44(2):521-32. doi: 10.1002/eji.201243291. Epub 2013 Dec 2.
The generation of CD4⁺Foxp3⁺ Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-β receptor 2 (Tgfbr2⁻/⁻ mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4⁺Foxp3⁺ Treg cells before they egressed to peripheral tissues. CD4⁺Foxp3⁺ thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2⁻/⁻ Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2⁻/⁻ Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-β signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.
胸腺中 CD4⁺Foxp3⁺Treg 细胞的产生对于免疫稳态和自身耐受至关重要。最近的研究表明，当存在 Th 相关转录因子和细胞因子时，Treg 细胞具有可塑性。然而，维持 Treg 细胞稳定性的机制尚不清楚。在这里，我们使用 T 细胞特异性缺失转化生长因子-β 受体 2（Tgfbr2⁻/⁻ 小鼠）的小鼠，确定 AKT 激活的限制是控制 Th1 炎症中 Treg 细胞稳定性的关键事件。AKT 调节在胸腺 CD4⁺Foxp3⁺Treg 细胞离开外周组织之前就已经明显。来自 Tgfbr2 缺失小鼠的胸腺 CD4⁺Foxp3⁺胸腺细胞表达高水平的 CXCR3 和 T-bet，并产生 IFN-γ 和 TNF-α。胸腺 Tgfbr2⁻/⁻Treg 细胞也表现出 AKT 通路的激活增加。增强的 AKT 活性诱导自然和诱导性 Treg 细胞中 IFN-γ 的表达。AKT 活性的抑制显著减弱了体内胸腺 Tgfbr2⁻/⁻Treg 细胞中 IFN-γ 和 TNF-α 的表达。此外，混合骨髓移植表明 TGF-β 信号以内在方式维持 Treg 细胞的稳定性。我们的结果表明 AKT 过度激活有助于 Treg 细胞向 Th1 表型的转化。
