Small molecule inhibition of Csk alters affinity recognition by T cells.
Small molecule inhibition of Csk alters affinity recognition by T cells.
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DOI：
10.7554/elife.08088
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发表时间：
2015-08-24
期刊：
影响因子：
7.7
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Manz BN;Tan YX;Courtney AH;Rutaganira F;Palmer E;Shokat KM;Weiss A
C末端Src激酶(CSK)是Src家族激酶(SFK)的主要负性调节因子，在控制基础受体和诱导性受体信号转导中起着至关重要的作用。为了研究CSK活性如何调节T细胞抗原受体(TCR)信号，我们利用了一只表达突变CSK(CskAS)的小鼠，它的催化活性被一个小分子特异性地、快速地抑制。在TCR刺激过程中抑制CskAS会导致TCR信号的增强和延长，并促进细胞增殖。抑制Cskas可增强微弱但严格同源的激动剂的激活作用。对CSK抑制的滴定显示，SFK活性的极小增加足以增强T细胞对弱激动剂的反应。CSK不仅在基础信号转导中发挥重要作用，而且在TCR信号转导阈值的设定和亲和力识别方面也发挥着重要作用。DOI：http://dx.doi.org/10.7554/eLife.08088.001免疫系统有‘T’细胞，当身体感染了病毒或细菌时，它会识别并启动针对该微生物的免疫反应。它们还可以发现并消灭癌细胞。微生物和癌细胞产生被称为抗原的分子，T细胞表面的蛋白质检测到这种分子被称为T细胞受体(TCR)。抗原识别导致TCR将信号传递到T细胞内部，从而触发免疫反应。TCR的活跃程度和它们传递信号的时间长度调节着免疫反应的大小。因此，开发控制TCRs活性的新药可能对治疗许多疾病有用。一种名为CSK的酶可以抑制参与各种不同过程的一小部分蛋白质的活动。CSK针对的一种蛋白质称为Lck，是激活T细胞免疫反应所必需的。然而，目前尚不清楚CSK与这种蛋白的相互作用是否会阻止TCRs释放信号，或者它是否会改变TCRs在传递信号之前需要激活的水平。Manz、Tan等人的研究成果。研究了具有CSK突变形式的小鼠的T细胞，这种突变形式的CSK被一种名为3-碘-苄基-PP1(3-IB-PP1)的药物抑制，但其他方面工作正常。当这些细胞在药物存在的情况下检测到抗原时，其TCR比未接触药物的细胞更高度激活，并在更长的时间内传递信号。这种药物特别增强了对非常弱的抗原的免疫反应，这些抗原在正常情况下可能不会激活T细胞。S等人的研究结果证实了CSK在T细胞激活中起着负面作用，并表明CSK可能是微调免疫反应的药物治疗的有用靶点。下一个挑战是找到一种可以抑制正常CSK酶的药物，并在小鼠和其他动物身上进行测试。DOI：http://dx.doi.org/10.7554/eLife.08088.002
The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (CskAS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of CskAS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of CskAS enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition. DOI: http://dx.doi.org/10.7554/eLife.08088.001 The immune system has ‘T’ cells that recognize when the body is infected with a virus or bacterium and mount an immune response that is targeted to that microbe. They can also find and eliminate cancer cells. The microbes and cancer cells produce molecules called antigens that are detected by proteins on the surface of the T cell called T cell receptors (TCR). Antigen recognition causes the TCRs to transmit signals to the inside of the T cell that trigger an immune response. The degree to which the TCRs are active, and the length of time that they transmit signals regulates the size of the immune response. Therefore, developing new drugs that manipulate the activity of TCRs could be useful to treat many diseases. An enzyme called Csk inhibits the activities of a small family of proteins involved in a variety of different processes. One protein that Csk targets is called Lck and is required for the activation of immune responses in T cells. However, it is not clear whether Csk interacting with this protein stops the release of signals from TCRs, or whether it alters the level to which TCRs need to be activated before they transmit the signals. Manz, Tan et al. studied T cells from mice that had a mutant form of Csk that is inhibited by a drug called 3-iodo-benzyl-PP1 (3-IB-PP1), but otherwise works normally. When these cells detected an antigen in the presence of the drug, its TCRs were more highly activated and transmitted signals for a longer period of time than cells not exposed to the drug. The drug especially enhanced immune responses to very weak antigens, ones that might not activate T cells under normal circumstances. Manz, Tan et al.'s findings confirm that Csk plays a negative role in the activation of T cells and suggest that Csk may be a useful target for drug therapies that aim to fine-tune immune responses. The next challenge is to find a drug that can inhibit normal Csk enzymes and test this in mice and other animals. DOI: http://dx.doi.org/10.7554/eLife.08088.002