The Pim kinases control rapamycin-resistant T cell survival and activation.
The Pim kinases control rapamycin-resistant T cell survival and activation.
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DOI：
10.1084/jem.20042020
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发表时间：
2005-01-17
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虽然Pim-1或Pim-2在过度表达时可以促进淋巴样转化，但这些激酶在免疫反应中的生理作用尚不确定。我们现在报道，来自皮姆-1−/−皮姆-2−/−动物的T细胞对免疫抑制剂雷帕霉素表现出意想不到的敏感性。细胞因子诱导的Pim-1和Pim-2促进淋巴细胞耐雷帕霉素存活。Pim激酶的内源性功能并不局限于调节细胞存活。与雷帕霉素靶TOR一样，Pim激酶也参与淋巴细胞生长和增殖的调控。尽管雷帕霉素在体外和体内对野生型T细胞扩增的影响很小，但它完全抑制Pim-1−/−Pim-2−/−细胞的反应。因此，内源性的Pim激酶水平是T细胞在雷帕霉素存在下产生免疫反应所必需的。调节T细胞生长和存活的雷帕霉素不敏感通路的存在对于理解雷帕霉素作为免疫调节药物的功能和开发补充免疫疗法具有重要意义。
Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics.