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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential Impact Of The Cd45 Juxtamembrane Wedge On Central And Peripheral T Cell Receptor Responses
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Differential Impact Of The Cd45 Juxtamembrane Wedge On Central And Peripheral T Cell Receptor Responses

机译:Cd45近膜楔对中枢和外周T细胞受体反应的差异影响

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摘要

The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phospha-tase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphopro liferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context.
机译:蛋白质酪氨酸激酶和磷酸酶的协同活性在调节T细胞受体(TCR)信号强度中起着核心作用。扰乱这种平衡,从而扰乱TCR信号的阈值,对T细胞的发育和功能产生了深远的影响。我们先前生成的小鼠在受体样蛋白酪氨酸磷酸酶CD45的近膜楔形中含有点突变。 CD45 E613R(WEDGE)突变显示出楔形细胞的关键负调控功能,导致了淋巴细胞原性增生性疾病(LPD)和狼疮样自身免疫综合症。现在,使用遗传,细胞和生化方法,我们证明CD45楔形物会影响T细胞的发育和功能。与增加的TCR信号强度一致,WEDGE小鼠增强了对CD4介导的疾病实验性自身免疫性脑炎(EAE)的阳性选择并增强了敏感性。这些与胸腺细胞中对TCR刺激的高反应性钙和pERK反应相对应,但令人惊讶的是,在外周T细胞中却没有,这些反应实际上被抑制了。总之,数据支持CD45楔在体内调节T细胞反应中的作用,并表明其作用取决于细胞环境。

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  • 作者单位

    Departments of Pediatrics, University of California, San Francisco, CA 94143;

    Departments of Medicine, University of California, San Francisco, CA 94143;

    Departments of Medicine, University of California, San Francisco, CA 94143 Departments of Howard Hughes Medical Institute, University of California, San Francisco, CA 94143;

    Departments of Pediatrics, University of California, San Francisco, CA 94143;

    Departments of Pediatrics, University of California, San Francisco, CA 94143;

    Departments of Pediatrics, University of California, San Francisco, CA 94143;

    Departments of Pediatrics, University of California, San Francisco, CA 94143;

    Departments of Neuroscience, University of California, San Francisco, CA 94143;

    Departments of Neuroscience, University of California, San Francisco, CA 94143;

    Departments of Medicine, University of California, San Francisco, CA 94143 Departments of Neuroscience, University of California, San Francisco, CA 94143 Departments of Microbiology and Immunology, University of California, San Francisco, CA 94143;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    autoimmunity; tyrosine phosphatase; tyrosine kinase; thymocyte development;

    机译:自身免疫;酪氨酸磷酸酶;酪氨酸激酶;胸腺细胞发育;

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