Towards an integrated understanding of the CD28/CTLA4 immune checkpoint in the regulation of autoimmunity

免疫系统包含许多强大的武器，可以保护我们免受威胁我们健康的微生物的持续攻击。不幸的是，像任何复杂的系统一样，它有时会出错，而不是保护我们，可以攻击我们自己的身体并造成损害。这种“附带损害”是导致自身免疫性疾病的原因，如1型糖尿病、类风湿性关节炎和多发性硬化症：负责的武器是我们免疫大军的一部分，只是在错误的时间出现在错误的地点。在这些疾病中启动自身免疫攻击的关键武器被称为T细胞。当科学家们探索哪些基因是导致自身免疫性疾病的原因时，他们发现了一种强烈的倾向，即告诉我们的T细胞发射或影响它们停止发射的能力的基因。使用动物模型进行的仔细实验也表明，仅仅通过将T细胞从一只小鼠转移到另一只小鼠就可能导致自身免疫性疾病。这提供了强有力的证据，表明T细胞是决定一个人是否患上自身免疫性疾病的关键因素。因此，正确理解告诉T细胞发射或停止发射的信号对于理解和治疗许多自身免疫性疾病至关重要。使用涉及4个分子开关的精确系统来做出该决定。这些开关中的两个（CD28和CTLA 4）是在T细胞上表达的受体，并且这些与在其他细胞上表达的2个结合配偶体（CD80和CD86）相互作用。正确使用这4种分子可能意味着生与死的区别。如果没有CD28，免疫应答就不能正确地建立，如果没有CTLA 4，免疫应答不加选择地激发，导致致命的炎症。虽然CD28促进免疫反应而CTLA4抑制免疫反应是非常清楚的，但为什么这些相反的开关共享相同的触发器（CD80和CD86）是一个完全的谜。从表面上看，似乎更直观的是让一个结合伴侣与CD28（开启开关）结合，另一个与CTLA 4（关闭开关）结合。然而，CD80和CD86都可以结合CD28和CTLA 4。那么，免疫系统是如何决定CD28或CTLA4获胜的呢？我们小组最近的工作在理解这一系统方面取得了实质性进展。我们发现CTLA4通过吸引CD80和CD86从而防止CD28被触发而起作用。这种模型与以前的想法有着根本的不同，它解释了系统的许多功能，直到现在都没有意义。以这种方式看待系统会促使我们提出不同的问题：为什么有两个绑定伙伴？它们都被CTLA4等效地吸走了吗？两者在移除后重新表达所需的时间是否相同？这对免疫反应的控制意味着什么？在本提案中，我们将解决这些问题和其他问题，以详细了解这一重要系统，并利用这些知识提出免疫疗法的新想法。我们在这个项目中所学到的将与各种免疫介导的疾病直接相关，从自身免疫到癌症，从疫苗接种到器官移植。

The immune system contains a number of powerful weapons that defend us from constant attacks by microbes that threaten our health. Unfortunately, like any complex system it sometimes goes wrong and instead of defending us, can attack our own body and cause damage. Such "collateral damage" is what causes autoimmune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis: the weapons responsible are part of our immune army performing their normal jobs, just in the wrong place at the wrong time. The key weapon that starts the autoimmune attack in these diseases is called a T cell. When scientists explored which genes are responsible for autoimmune diseases, they identified a strong bias towards genes that tell our T cells to fire or affect their ability to stop firing. Careful experiments using animal models have also shown that it is possible to cause autoimmune diseases just by transferring T cells from one mouse to another. This provides strong evidence that T cells are critical players in determining whether a person develops an autoimmune disease. Properly understanding the signals that tell T cells to fire or cease firing is therefore critical to understanding and treating many autoimmune diseases. A precise system involving 4 molecular switches is used to make this decision. Two of these switches (CD28 and CTLA4) are receptors expressed on the T cell and these interact with 2 binding partners (CD80 and CD86) expressed on other cells. Correct use of these 4 molecules can mean the difference between life and death. Without CD28 immune responses cannot be mounted properly and without CTLA4 the immune response fires indiscriminately causing lethal inflammation. Whilst it is very clear that CD28 promotes immune responses and CTLA4 inhibits them, why these opposing switches share the same triggers (CD80 and CD86) is a complete mystery. At face value, it would seem more intuitive to have one binding partner to engage CD28 (the on switch) and another to engage CTLA4 (the off switch). However both CD80 and CD86 can bind to both CD28 and CTLA4. How then does the immune system decide whether CD28 or CTLA4 wins out? Recent work from our groups has made substantial progress in understanding this system. We discovered that CTLA4 works by hoovering up CD80 and CD86 thereby preventing CD28 from being triggered. Such a model is fundamentally different to previous ideas and explains many features of the system that until now did not make sense. Viewing the system in this way prompts us to ask different questions: Why are there 2 binding partners? Are they both equivalently hoovered up by CTLA4? Do both take the same amount of time to be re-expressed after removal? What does this mean for the control of immune responses? In this proposal we will address these and other questions to generate a detailed understanding of this important system and use this knowledge to come up with new ideas for immune therapies. What we learn in this project will be of direct relevance to a wide variety of immune mediated conditions from autoimmunity to cancer and vaccination to organ transplantation.