Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma
Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma
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DOI：
10.1002/eji.200324048
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发表时间：
2003-08-01
影响因子：
5.4
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Rathmell, JC;Elstrom, RL;Thompson, CB
调节基础T细胞大小和代谢活性的机制尚不确定。由于磷脂酰肌醇-3磷酸激酶（PI 3 K）和Akt（PKB）途径已在模型生物中显示出调节细胞大小和代谢，我们产生了在T细胞中表达组成型活性形式的Akt（豆蔻酰化Akt，mAkt）的转基因小鼠。与对照T细胞相比，幼稚转基因T细胞增大并且具有增加的糖酵解速率。此外，mAkt转基因T细胞在体外培养时抵抗忽视死亡。活化后，mAkt转基因T细胞对通过CD 28的共刺激的依赖性低于对照细胞，并且在不存在CD 28连接的情况下可以快速生长并分泌细胞因子。此外，mAkt的转基因表达导致CD 4 T细胞和B细胞随着年龄的增长而积累。许多老年mAkt转基因小鼠也出现自身免疫性，肾小球上有免疫球蛋白沉积，淋巴瘤发生率增加。总之，这些数据表明Akt活化足以增加基础T细胞大小和代谢。Akt增强T细胞代谢和更快速的CD 28非依赖性T细胞生长可能有助于过量免疫细胞的积累以及淋巴瘤和自身免疫的发展。
The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphaticlylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoirnmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoirnmunity.