TNF, a protein that drives inflammation, can either keep T cells alive or instruct them to self-destruct, and this research aims to understand exactly how it makes that choice. This matters because TNF-blocking drugs are widely used to treat autoimmune diseases like arthritis and inflammatory bowel disease, yet they fail in about 30% of arthritis patients and can even worsen some conditions. The problem is that scientists do not fully understand how TNF controls T cells—the immune cells that orchestrate attacks on infections and, when overactive, drive autoimmune damage. The researchers have already shown that TNF keeps T cells alive not by activating a genetic survival programme, as long assumed, but by directly blocking death-inducing proteins inside the cells. This raises fundamental questions about what the TNF-driven genetic programme actually does. If this research succeeds, it could reveal why some patients do not respond to TNF inhibitors and suggest ways to predict who will benefit. It might also point toward more targeted therapies that preserve TNF’s beneficial effects—fighting infection—while blocking its damaging inflammatory side effects. This is fundamental science: understanding the molecular wiring of a central immune switch, with potential long-term payoffs for treating chronic inflammatory diseases.
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My laboratory studies the biology of an important 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. TNF is a protein made by many types of cells during immune responses and plays an important role in stimulating immune cells to fight invading organisms. Because TNF promotes immune activity, it also makes it a potent inducer of inflammation, that can also result in serious 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 several clinical therapies that work by specifically blocking TNF and these have proved highly effective in a number of different diseases. However, we do not fully understand how this therapy works. While some individuals with arthritis respond well to TNF inhibition, about 30% of sufferers gain no benefit. In other diseases, attempted TNF treatment has been unsuccessful or exacerbated symptoms. Because many of these diseases involve an over-active 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. New results from my lab have revealed that both generation and function of T cells in normal healthy people requires TNF. However, TNF is a double edged sword. On one hand, it can keep cells alive, but in other circumstance, it can give instructions for cells to kill themselves. In the last few years, my lab has explored how TNF controls life/death decision in T cells. TNF can regulate the genetic code in T cells to control how the cells behave, and for a long time, it was thought that the T cells were kept alive by activating a genetic survival programme. We showed that survival of T cells does not depend on TNF controlled genetic programme. Rather, TNF can directly inhibit death inducing proteins inside T cells, keep cells alive. This raises fundamental questions about how TNF controls what T cells do during immune responses. How does TNF block cell death ? What is the TNF induced genetic programme for, if it is not needed to keep cells alive ? Our work uses sophisticated mouse genetics to address these questions, but also raises the crucial question, do human T cells also work in the same way ? Our proposed research therefore aims to : 1. To understand the functions of TNF and related factors in controling T cells during influenza viral infection and inflammatory bowl disease in mice 2. To determine the molecular mechanisms by which TNF controls their behaviour. 3. Investigate the genetic mechanisms by which TNF controls human T cells.
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