Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome
Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome
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DOI：
10.4049/jimmunol.178.3.1363
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Luehder, Fred
中科院分区：
文献类型：
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作者：
Dennehy, Kevin M.;Elias, Fernando;Luehder, Fred
几乎所有生理性T细胞反应都需要克隆型TCR与MHC/Ag和CD 28通过其配体CD 80/86的共刺激接合。CD 28提供的信号是定性独特的还是定量放大TCR信号传导的尚不清楚。在这项研究中，我们使用超激动性CD 28抗体，诱导T细胞增殖，而没有TCR共连接，以确定如何CD 28有助于有丝分裂反应。我们表明，促有丝分裂的CD 28信号需要，但不激活近端TCR组分TCR和Zap-70激酶。在缺乏近端TCR信号传导的细胞系中，CD 28通路的早期缺陷是衔接分子SLP-76的磷酸化，我们表明这对于募集导致Ca 2+通量和IL-2产生的交换因子Vav至关重要。导致Vav磷酸化减少的CD 28点突变也导致Ca 2+通量、IL-2产生和Tec激酶磷酸化缺陷。使用Vav 1缺陷小鼠，我们进一步证明了Vav 1对有效增殖，IL-2产生和Ca 2+通量的重要性。我们的研究结果表明，CD 28信号在SLP-76信号体水平上进入TCR信号通路。
Almost all physiological T cell responses require costimulation-engagement of the clonotypic TCR with MHC/Ag and CD28 by its ligands CD80/86. Whether CD28 provides signals that are qualitatively unique or quantitatively amplify TCR signaling is poorly understood. In this study, we use superagonistic CD28 Abs, which induce T cell proliferation without TCR coligation, to determine how CD28 contributes to mitogenic responses. We show that mitogenic CD28 signals require but do not activate the proximal TCR components TCR and Zap-70 kinase. In cell lines lacking proximal TCR signaling, an early defect in the CD28 pathway is in phosphorylation of the adaptor molecule SLP-76, which we show is essential for recruitment of the exchange factor Vav leading to Ca2+ flux and IL-2 production. Point mutations in CD28 that result in diminished Vav phosphorylation also result in defective Ca2+ flux, IL-2 production, and Tec-kinase phosphorylation. Using Vav1-deficient mice, we further demonstrate the importance of Vav1 for efficient proliferation, IL-2 production, and Ca2+ flux. Our results indicate that CD28 signals feed into the TCR signaling pathway at the level of the SLP-76 signalosome.