Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition
Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition
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DOI：
10.4049/jimmunol.178.9.5443
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Tsichlis, Philip N.
中科院分区：
文献类型：
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作者：
Mao, Changchuin;Tili, Esmerina G.;Tsichlis, Philip N.
前TCR信号调控胸腺细胞从双阴性(DN)3到DN4，然后到双阳性(DP)阶段。在这项研究中，我们发现前TCR信号激活Akt，药物抑制PI3K/Akt通路，或联合消融Akt1和Akt2，以及较小程度的Akt1和AKT3，干扰DN3的分化和DP胸腺细胞的积累。联合消融Akt1和Akt2可抑制DN4细胞的增殖，同时联合消融所有Akt亚型也可抑制所有胸腺细胞的存活。最后，Akt1和Akt2的联合消融抑制了DP胸腺细胞的存活。结构性活性的Lck-Akt1转基因则有相反的效果。我们的结论是，在它们被前TCR信号激活后，Akt1、Akt2和AKT3在较小程度上促进了糖尿病肾病胸腺细胞向DP阶段的过渡，部分是通过促进P-选择细胞的增殖和存活。AKT1和Akt2也通过促进DP胸腺细胞的存活而参与分化过程。
Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing P-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.