Regulation of T cell development and function by the TNF induced signalling

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.

TNF is an inflammatory mediator implicated in the pathogenesis of a host autoimmune and inflammatory diseases in humans. In some of these conditions, blocking TNF activity has proved a clinically effective treatment. T cell immunity is implicated in many of the clinical settings in which TNF targeted intervention is being employed or considered, and yet our understanding of TNF signalling in T cells and how it may modulate their development and function is still rudimentary. Our recent work shows that TNF induced activation of NF-kB is critical for development of new T cells, and that making functionally mature T cells depends on these signals. Our hypothesis is that TNF and related family members deliver signals to developing thymocytes that regulate the functional maturation of new T cells, and may also mediate a similar regulatory role during T cell activation, affecting T cell survival and differentiation. By these two mechanisms, TNF signalling can influence both quality and quantity of T cell responses thereby influencing the outcome of adaptive immune responses. Our aims are therefore to :

1. To understand how TNF-family signalling controls functional maturation of new T cells in the thymus,
2. To determine the mechanisms by which TNF-family induced survival, death and differentiation signals regulate T cell activation, differentiation of effectors and generation of memory

Our proposed studies will lead to fundamental advances in our understanding of how TNF signalling regulates both immune reconstitution and T cell activation and memory formation and promises to substantially improve our understanding of the full impact of TNF interventions on the T cell compartment as a whole. Improved understanding of TNF signalling in T cells will lead to a better understanding of how therapeutic intervention of TNF and its downstream signalling pathways can be best applied to modify T cell responses in a desirable manner and to a beneficial clinical outcome.

Our proposal aims to address fundamental questions concerning the biology of TNF signalling in T cells and are likely to be of broad interest not only to those working in the immediate fields, but also to a broader scientific, clinical and lay audiences. We expect this work to impact on academic scientists outside of our immediate professional circle, clinical scientists interested in the transfer of basic research of clinical relevance to the clinic and also the general public, including school children considering future careers.

Academic scientists : This research will provide important new data on the regulation of TNF signalling in T cells and the mechanisms by which NF-kB and RIPK1 signalling regulates T cell survival and differentiation. This information will be of benefit to academic scientists working across the fields of cell signalling and immunology, who can build on our work within their own spheres of interest. In the short-term, we expect to benefit from this by opening up new networks and collaborations with international scientists. In the longer term we hope that our research will contribute to the realisation of funding to improve health by informing novel applications or modifications to optimise anti-TNF treatment. Dissemination of the data and preparation of manuscripts for publication will provide the PDRA working on this project with key communication skills that are essential in all employment sectors.

Translational applications : Understanding how TNF signalling is regulated in T cells, and how these signals affects maturation and function of T cells will be of interest to clinical scientists who can build on our work, for the improvement of patient experience and quality of life. While we are addressing basic biological questions, because TNF is an important clinical target, we intend to build upon our findings by developing collaborations with translational researchers so we can further explore how our findings might influence current applications, such as treatment of arthritis, and new applications of anti-TNF therapy and for understanding the impact of NF-kB mutations in patients with common variable immunodeficiency (CVID). This would occur in the latter half of the grant, when we have a clearer understanding of the biology of TNF and downstream NF-kB and RIPK1 signalling in T cells and can formulate testable hypotheses to take into a human/clinical context.

The public/future scientists : We believe that the basic question driving this application will be of interest to the wider public - how and why does inflammation potentially affect the function of their immune systems ? How do inflammatory factors such as TNF affect the response of T cells in health and disease ? Because of the numerous clinical applications of anti-TNF treatment in conditions that affect large numbers of people, but is not successful in all cases, makes the subject of direct relevance and interest to many people. We hope that public will benefit by understanding the importance of fundamental research, and how it can lay important foundations for translation into clinic that can impact the nations health. We hope that communicating our research to children will engage and enthuse them to pursue a career in science. We expect both PDRAs to actively engage in public engagement opportunities within the department, and this will benefit their own presentation and communication skills to lay audience.