HIP-55 is important for T-cell proliferation, cytokine production, and immune responses
HIP-55 is important for T-cell proliferation, cytokine production, and immune responses
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DOI：
10.1128/mcb.25.16.6869-6878.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Tan, TH
中科院分区：
文献类型：
--
作者：
Han, J;Shui, JW;Tan, TH
T 细胞受体 (TCR) 的参与会触发一系列信号事件，从而导致 T 细胞激活。 HIP-55（SH3P7 或 mAbp1）是一种肌动蛋白结合衔接蛋白，与 ZAP-70 相互作用并被 ZAP-70 酪氨酸磷酸化，ZAP-70 是 TCR 信号传导的重要近端蛋白酪氨酸激酶。 HIP-55 对于 TCR 信号传导诱导的 JNK 和 HPK1 激活非常重要。在这项研究中，我们报告了 HIP-55 敲除小鼠的产生和表征。我们发现 HIP-55 基因敲除小鼠能够存活并具有生育能力，但在出生后 4 周内体重下降，死亡发生率增加。 HIP-55 敲除小鼠的淋巴器官显示出与野生型小鼠相当的细胞结构和 T 细胞发育。 HIP-55 敲除 T 细胞表现出 T 细胞增殖缺陷、细胞因子产生减少以及 TCR 刺激诱导的激活标记物上调减少。 HIP-55 敲除 T 细胞中 TCR 内化略有增加。这些表型伴随着免疫反应的减少，包括 HIP-55 敲除小鼠中抗原特异性抗体的产生和 T 细胞增殖。 TCR 诱导的信号转导事件，包括 LAT/磷脂酶 C gamma 1 磷酸化和 HPK1/JNK 激活，在 HIP-55 敲除 T 细胞中部分缺陷。这些结果证明了 HIP-55 作为 TCR 信号传导和免疫系统中的衔接蛋白的重要性。
Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase C gamma 1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.