T cells—the immune system’s central coordinators—need a hormone called tumour necrosis factor (TNF) to be made and to function properly, even in healthy people with no infection. This finding is surprising because TNF is best known as a driver of inflammation, and blocking it with drugs has become a standard treatment for diseases like arthritis and inflammatory bowel disease. Yet about 30% of arthritis patients get no benefit from TNF-blocking therapies, and in some conditions the drugs can even make symptoms worse. The problem is that no one understands exactly how TNF controls T cells—the very cells that orchestrate immune attacks. Without that knowledge, doctors cannot predict who will respond to treatment or why. This project will use genetic mouse models to trace the molecular messengers inside T cells that carry TNF’s signals. If the researchers succeed, they will reveal the fundamental mechanisms by which TNF shapes T cell production and immune responses. That deeper understanding could eventually help clinicians decide when TNF-blocking therapies will work, and may point to new drug targets inside cells for fine-tuning T cell activity—rather than simply shutting down TNF entirely.
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My laboratory studies the biology of a particular blood cell of the immune system - the T cell. These cells are made throughout life and circulate around the body via the blood stream. When they encounter an invading infection they recognise, they react to that infection by orchestrating an immune response against the invader, organising a host of different immune cell types to eliminate the infection. They are therefore a central component of the immune system. The aim of my laboratory is to understand how T cells are made throughout life and how they are kept in an optimal functioning state ready to react to invading organisms. New experiments in my lab have revealed that both synthesis and function of T cells in normal healthy people depends on their stimulation with a immune hormone, called tumour necrosis factor (TNF). TNF is mostly usually synthesised by various immune cells during immune responses and plays an important role in stimulating cells to fight invading organisms. Therefore, it is surprising that we find an important role for TNF in making T cells in normal healthy individuals in the absence of infection. Because TNF promotes immune reactivity, it also makes it a potent inducer of inflammation, and when made in excessive quantities can result in serious immune mediated damage to tissues and organs. Consequently, excessive TNF activity has been linked with causing damage in various diseases including arthritis, inflammatory bowel disease and psoriasis to name some. There are now several clinical therapies that work by specifically blocking the activity of TNF and these have proved highly effective in a number of different diseases such as arthritis. However, we do not fully understand how this therapy works. While some individuals with arthritis respond well to TNF inhibition, about 30% of suffers gain no benefit. In other diseases, attempted TNF treatment has been unsuccessful or exacerbated symptoms. Because many of these diseases involve an over-active the immune system, T cells are also thought to be involved. T cells both synthesise and react to TNF, but our knowledge of how TNF might be influencing these critical immune cells is greatly lacking. Given the importance of TNF in inflammation and disease, our new results showing that TNF is important for production and function of T cells in healthy, uninfected individuals therefore raises many important questions about the mechanisms by which TNF controls T cells and whether these mechanisms are a help or a hinderance during immune responses to infections or in disease conditions. Our proposed research therefore aims to : 1. To understand the mechanisms by which TNF controls generation of new T cells. 2. To determine the mechanisms by which TNF controls the size and quality of immune responses to infections. When TNF stimulates T cells, it triggers a variety of different messenger proteins inside the cell that transmit signals within the cell that influence the genetic programming of the cell and control its behaviour and function. We will therefore study the role of different messengers to understand how TNF controls T cell behaviour. We will do this using genetic mouse models, in which T cells specifically lack individual messenger proteins. It is our hope that by using these powerful experimental approaches to pursue these aims, we will gain a deep understanding of the mechanisms by which TNF controls T cells. We will develop new understanding about how TNF functions, and how clinical treatments that target TNF may affect T cells, both for there generation and their function during immune responses. Better understanding will help predict how and when TNF therapy is useful, while studying the processes by which TNF sends signals into cells may help identify drug targets within the cell that can be targeted to modulate T cell activity.
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