Negative regulation of interleukin-2 and p38 mitogen-activated protein kinase during T-cell activation by the adaptor ALX
Negative regulation of interleukin-2 and p38 mitogen-activated protein kinase during T-cell activation by the adaptor ALX
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DOI：
10.1128/mcb.02067-05
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Shapiro, Virginia Smith
中科院分区：
文献类型：
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作者：
Perchonock, Claire E.;Fernando, Melissa C.;Shapiro, Virginia Smith
初始T细胞的激活需要T细胞受体(TCR)和CD28产生的协同信号。我们以前发现了一个新的接头ALX，当它在Jurkat T细胞中过表达时，可以抑制TCR/CD28对白细胞介素2(IL-2)启动子的激活，这表明它是T细胞激活的负调控因子。为了进一步了解ALX的生理作用，我们建立了ALX缺陷小鼠。来自ALX缺陷小鼠的纯化T细胞对TCR/CD28刺激反应增加了IL-2的产生、CD25的表达和增殖。ALX缺陷小鼠体内注射卵清蛋白完全弗氏佐剂，然后在体外重新刺激，也观察到IL-2的产生和增殖增加。与我们最初的过度表达研究一致，这些数据表明ALX是T细胞激活的负调节因子。而TCR/CD28介导的磷酸化酪氨酸诱导、细胞外信号调节激酶1/2、Jun N末端蛋白激酶、I kappa B激酶α/β和AM的激活没有改变，而p38丝裂原活化蛋白激酶及其上游调节因子MKK3/6在ALX缺乏的脾细胞中被结构性激活。ALX缺陷小鼠的表型类似于跨膜适配器LAX缺陷小鼠的表型，并且ALX和LAX蛋白之间存在关联。这些结果表明，ALX与LAX一起，通过抑制p38来负向调节T细胞的激活。
Activation of naive T cells requires synergistic signals produced by the T-cell receptor (TCR) and by CD28. We previously identified the novel adaptor ALX, which, upon overexpression in Jurkat T cells, inhibited activation of the interleukin-2 (IL-2) promoter by TCR/CD28, suggesting that it is a negative regulator of T-cell activation. To further understand the physiological role of ALX, ALX-deficient mice were generated. Purified T cells from ALX-deficient mice demonstrated increased IL-2 production, CD25 expression, and proliferation in response to TCR/CD28 stimulation. Enhanced IL-2 production and proliferation were also observed when ALX-deficient mice were primed in vivo with ovalbumin-complete Freund's adjuvant and then restimulated ex vivo. Consistent with our initial overexpression studies, these data demonstrate that ALX is a negative regulator of T-cell activation. While TCR/CD28-mediated activations of phosphotyrosine induction, extracelllular signal-regulated kinase 1/2, Jun N-terminal protein kinase, I kappa B kinase alpha/beta, and AM were unaltered, constitutive activation of p38 mitogen-activated protein kinase and its upstream regulators MKK3/6 were observed for ALX-deficient splenocytes. The phenotype of ALX-deficient mice resembled the phenotype of those deficient in the transmembrane adaptor LAX, and an association between ALX and LAX proteins was demonstrated. These results suggest that ALX, in association with LAX, negatively regulates T-cell activation through inhibition of p38.