Defining non-redundant functions of glycogen synthase kinase (GSK)-3 alpha and GSK-3 beta in T cell subsets that control tumour growth

我们的免疫系统保护我们免受大量、频繁的感染。现在人们认识到免疫系统也有助于发现和摧毁癌症的早期阶段。了解免疫系统的工作原理是提高我们对如何控制感染和癌症的认识的关键，例如通过设计增强免疫细胞作用的治疗方法。我们对一组被称为T细胞的白细胞感兴趣。这些细胞在组织中巡逻，寻找被病毒感染或癌变的细胞。在检测癌细胞时，T细胞做三件事；它们直接杀死癌细胞，释放激素样分子，称为细胞因子和趋化因子，招募其他类型的白细胞到该部位，帮助其他免疫细胞杀死肿瘤并防止其扩散。我们感兴趣的是这些辅助细胞以及它们是如何被调节的。事实上，这些辅助性T细胞由几种不同的类型组成，它们都有不同的作用和作用部位。尽管免疫系统可以检测并杀死肿瘤，但癌细胞最终会逃脱免疫系统的注意。它们通过各种机制来降低T细胞和其他免疫成分的活性。我们对一种叫GSK-3的酶感兴趣。这是一个存在于所有细胞中的分子开关，它控制细胞活动的开启和关闭。我们已经证明，在癌症中，GSK-3会关闭T细胞。如果我们用药物抑制GSK-3，那么开关就会重新打开，T细胞就会再次攻击肿瘤。我们的研究结果提出了一种治疗癌症的策略。关闭GSK-3的药物可能有助于增强患者的免疫系统并消除癌症。然而，我们对GSK-3的作用知之甚少，事实上，所有细胞中都有两种类型的GSK-3，它们的功能并不完全相同。此外，由于GSK-3在所有组织中表达，目前的GSK-3不是针对免疫细胞的，可能是有毒的。在本文中，我们将使用细胞和分子方法结合癌症模型来了解GSK-3对辅助性T细胞的作用。通过确定由GSK-3调节的精确T细胞类型以及发现GSK-3调节的其他分子，我们希望在未来能够设计出新的改进药物，可以用于患者通过激活免疫系统来消除癌症。

Our immune system protects us against numerous, frequent infections. It is now recognised that the immune system also helps to detect and destroy the early stages of cancer. Understanding how the immune system works is key to improving our knowledge of how infections and cancer can be controlled, for example by designing treatments that enhance the action of immune cells.We are interested in a group of white blood cells known as T cells. These cells patrol the tissues and look out for cells that have become infected with viruses or which have become cancerous. On detecting cancer cells, T cells do three things; they kill the cancer cells directly, they release hormone-like molecules called cytokines and chemokines that recruit other types of white blood cell to the site and they help these other immune cells to kill the tumour and prevent its spread. We are interested in these helper cells and how they are regulated. In fact these helper T cells are comprised of several different types, all with differing roles and sites of action. Although the immune system can detect and kill tumours, cancer cells eventually escape the attention of the immune system. They do this by a variety of mechanisms which turn down the activity of the T cells and other immune components. We are interested in an enzyme called GSK-3. This is a molecular switch present in all cells which turns cell activity on and off. We have shown that in cancer, GSK-3 switches off T cells. If we inhibit GSK-3 with drugs then the switch is turned back on and the T cells once again attack the tumour. Our results suggest a strategy to treat cancer. Drugs that switch off GSK-3 might help to boost the patient's immune system and eliminate the cancer. However, we know very little about GSK-3 action and in fact there are two types of GSK-3 in all cells and they do not have exactly the same functions. Furthermore, because GSK-3 is expressed in all tissues, current GSK-3 are not specific to immune cells and can be toxic. In the proposed here we will use cellular and molecular methods coupled with cancer models to understand the action of GSK-3 on helper T cells. By identifying the precise T cell types that are regulated by GSK-3 and by finding other molecules that GSK-3 regulates we hope in the future to be able to design new improved drugs that could be used in patients to eliminate their cancer by activating their immune system.