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

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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.