ANERGIC T-LYMPHOCYTE CLONES HAVE ALTERED INOSITOL PHOSPHATE, CALCIUM, AND TYROSINE KINASE SIGNALING PATHWAYS
ANERGIC T-LYMPHOCYTE CLONES HAVE ALTERED INOSITOL PHOSPHATE, CALCIUM, AND TYROSINE KINASE SIGNALING PATHWAYS
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DOI：
10.1073/pnas.91.1.38
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发表时间：
1994-01-04
影响因子：
11.1
通讯作者：
FITCH, FW
中科院分区：
文献类型：
--
作者：
GAJEWSKI, TF;QIAN, DP;FITCH, FW
T（H）1辅助T淋巴细胞的完全活化需要特异性T细胞抗原受体（TCR）的连接和由在特定抗原呈递细胞上表达的共刺激分子提供的第二信号。单独通过TCR复合物的刺激产生随后的无反应状态，其特征在于不能产生白细胞介素2。我们在这里报告说，这种无反应性细胞表现出多种改变TCR相关的信号。在无反应性细胞中，细胞内游离钙和1，4，5-三磷酸磷脂酰肌醇的基础水平升高，并且在随后的再刺激后，该水平未能显著增加。对磷脂酶C-gamma 1的检查揭示了翻译后修饰的证据，与该分子的酪氨酸磷酸化增加相关。与未处理的细胞相比，从全细胞裂解物中鉴定的其他底物的酪氨酸磷酸化也发生了变化，表明净酪氨酸激酶活性发生了变化。虽然TCR/CD 3或Lck免疫沉淀物中存在的激酶活性水平在诱导无能后适度改变，但无能细胞中特异性Fyn相关酪氨酸激酶活性显著增加，并且与Fyn共免疫沉淀的110-kDa蛋白的磷酸化增加。这些结果与无反应性T（H）1淋巴细胞显示TCR介导的酪氨酸激酶活性的根本改变的模型一致，与磷脂酶C-γ 1、肌醇磷酸和细胞内游离钙的变化相关。
Full activation of T(H)1 helper T lymphocytes requires ligation of the specific T-cell antigen receptor (TCR) and a second signal provided by costimulator molecule(s) expressed on particular antigen-presenting cells. Stimulation via the TCR complex alone generates a subsequent unresponsive state characterized by an inability to produce interleukin 2. We report here that such anergic cells exhibit multiple alterations in TCR-associated signaling. The basal levels of intracellular free calcium and phosphatidylinositol 1,4,5-trisphosphate are elevated in anergic cells, and the levels fail to increase significantly upon subsequent restimulation. Examination of phospholipase C-gamma1 reveals evidence for post-translational modification, correlating with increased tyrosine phosphorylation of the molecule. Tyrosine phosphorylation of additional substrates identified from whole-cell lysates also is altered compared to untreated cells, suggesting a modification in net tyrosine kinase activity. Although the level of kinase activity present in TCR/CD3 or Lck immunoprecipitates is modestly altered after induction of anergy, there is a dramatic increase in specific Fyn-associated tyrosine kinase activity in anergic cells and increased phosphorylation of a 110-kDa protein that is coimmunoprecipitated with Fyn. These results are consistent with a model in which anergic T(H)1 lymphocytes display a fundamental alteration in TCR-mediated tyrosine kinase activity, associated with changes in phospholipase C-gamma1, inositol phosphates, and intracellular free calcium.