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Intracellular signal transduction of activated T cells and anergic T cells

活化 T 细胞和无反应 T 细胞的细胞内信号转导

基本信息

批准号：
11670276
负责人：
FUJIMAKI Wakae
金额：
$ 2.3万
依托单位：
Tokyo Woman's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670276/
关键词：
bacterial super-antigen human T-cell post-thymi c maturation signal transduction Lck CD45 T-cell subsets T細胞細胞内シグナル伝達機構

项目摘要

Human T cells show different biological responses according to T-cell maturation or subsets when stimulated with bacterial superantigens. We addressed the question why the T cells response in different way by comparing signal transduction.1. Human thymic CD1a^-CD4^+ T cells in the final stage of thymic maturation are susceptible to anergy induced by bacterial superantigens, whereas adult peripheral blood (APB) CD4^+ T cell are not only induced to anergic state but also exhibit high responses by restimulation. The tyrosine kinase activity of lck increased after restimulation in APB CD4^+ T-cell blasts but not in thymic CD4^+ T-cell blasts. The Lck was highly tyrosinphosphorylated in both types of T-cell blasts before restimulation. After restimulation, it was markedly dephosphorylated in APB CD4^+ T-cell blasts but not in thymic CD4^+ T-cell blasts. Confocal microscopy demonstrated that colocalization of Lck and CD45 was induced in restimulated APB CD4^+ T-cell blasts but not in thymic CD4^+ T-cell blasts. Further, remarkable accumulation of Lck in the membrane raft was observed in restimulated APB CD4^+ T-cell blasts but not in thymic CD4^+ T-cell blasts. These data indicate that interaction between Lck and CD45 is important for T- cell activation and that the interaction is suppressed physically in thymic CD4^+ T-cell blasts and plays a critical role in sustaining an anergic state.2. Next, we examined superantigen-induced responses of APB CD4^+ and CD8^+ T-cell subsets in vitro. The proliferative response and IL-2/IL-4 production were higher in CD4^+ T-cell subset than in CD8^+ T-cell subset, while IFN-y production and cytotoxic activity on MHC class II^+ cells were higher in the CD8^+ subset than in the CD4^+ subset. These data indicate that CD4^+ and CD8^+ 1-cell subsets are activated by bacterial superantigens in specific ways. Now we try to confirm that Lck regulation is related with the different responses.

当细菌超抗原刺激时，人类T细胞根据T细胞的成熟程度或亚群表现出不同的生物学反应。我们通过比较信号传导解决了为什么T细胞以不同的方式做出反应的问题。处于胸腺成熟末期的人胸腺CD1a^-CD4^+T细胞对细菌超抗原诱导的无能反应敏感，而成人外周血(APB)中的CD1a^-CD4^+T细胞不仅被诱导为无能状态，而且在再刺激下表现出较高的反应性。APB CD_4~+T细胞重新刺激后，LCK的酪氨酸激酶活性增加，而胸腺CD_4~+T细胞则无明显变化。在重新刺激之前，Lck在两种类型的T细胞中都高度酪氨酸磷酸化。经再刺激后，APB的CD_4~+T细胞显著去磷酸化，而胸腺CD_4~+T细胞则不明显。共聚焦显微镜显示，Lck和CD45在重新刺激的APB CD4^+T细胞中被诱导共定位，而在胸腺中不被诱导。此外，在重新刺激的APB CD4^+T细胞中观察到Lck在膜筏中的显著积聚，而在胸腺中则没有。这些数据表明，LCK和CD45之间的相互作用对于T细胞的激活是重要的，这种相互作用在胸腺CD4^+T细胞母细胞中受到物理抑制，并在维持无能状态中发挥关键作用。接下来，我们在体外检测了APB的超抗原诱导的CD4^+和CD8^+T细胞亚群的反应。CD8+T细胞亚群的增殖反应和IL-2/IL-4的产生高于CD8+T细胞亚群，而CD8+T细胞亚群的干扰素-γ的产生和对MHC II^+细胞的细胞毒活性高于CD8+T细胞亚群。这些数据表明，细菌超抗原以特定方式激活了CD4^+和CD8^+1-细胞亚群。现在我们试图证实Lck的调节与不同的反应有关。