Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3.
Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3.
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DOI：
10.1084/jem.192.1.99
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发表时间：
2000-07-03
影响因子：
15.3
通讯作者：
Ohashi, P S
中科院分区：
文献类型：
--
作者：
Ohteki, T;Parsons, M;Zakarian, A;Jones, R G;Nguyen, L T;Woodgett, J R;Ohashi, P S
糖原合成酶激酶(GSK)-3是一种蛋白丝氨酸/苏氨酸激酶，在多种生物体中调节分化和细胞命运。本研究考察了GSK-3在抗原特异性T细胞反应中的作用。利用P14 T细胞受体（TCR）转基因小鼠的静息T细胞（对淋巴细胞性绒毛膜脑膜炎病毒和H-2Db具有特异性），我们证实了GSK-3β在体外病毒肽特异性刺激后被丝氨酸磷酸化灭活。为了进一步研究GSK-3的作用，我们制作了一种逆转录病毒载体，表达GSK-3β的组成活性形式，该形式在调节氨基酸丝氨酸9 （GSK-3β a9）上有丙氨酸替代。逆转录病毒转导P14 tcr转基因骨髓干细胞，然后重组，导致骨髓嵌合小鼠中GSK-3βA9的表达。嵌合小鼠的T细胞增殖和白细胞介素-2的产生减少。相反，在GSK-3抑制剂锂的存在下进行的体外实验导致T细胞增殖显著延长，IL-2产生增加。此外，在锂的存在下，我们发现活化T细胞的核因子（NF-AT）c在抗原特异性刺激T细胞后仍留在细胞核中。总之，这些数据表明GSK-3负调控T细胞反应的持续时间。
Glycogen synthase kinase (GSK)-3 is a protein serine/threonine kinase that regulates differentiation and cell fate in a variety of organisms. This study examined the role of GSK-3 in antigen-specific T cell responses. Using resting T cells from P14 T cell receptor (TCR)-transgenic mice (specific for the lymphocytic choriomeningitis virus and H-2Db), we demonstrated that GSK-3β was inactivated by serine phosphorylation after viral peptide–specific stimulation in vitro. To further investigate the role of GSK-3, we have generated a retroviral vector that expresses a constitutively active form of GSK-3β that has an alanine substitution at the regulatory amino acid, serine 9 (GSK-3βA9). Retroviral transduction of P14 TCR–transgenic bone marrow stem cells, followed by reconstitution, led to the expression of GSK-3βA9 in bone marrow chimeric mice. T cells from chimeric mice demonstrate a reduction in proliferation and interleukin (IL)-2 production. In contrast, in vitro assays done in the presence of the GSK-3 inhibitor lithium led to dramatically prolonged T cell proliferation and increased IL-2 production. Furthermore, in the presence of lithium, we show that nuclear factor of activated T cells (NF-AT)c remains in the nucleus after antigen-specific stimulation of T cells. Together, these data demonstrate that GSK-3 negatively regulates the duration of T cell responses.