Neutrophil exacerbation of T cell dysfunction in autoimmunity

In this project, I am aiming to understand how damaging immune responses develop and persist in autoimmune conditions such as Multiple Sclerosis and Crohn’s disease. These conditions affect millions in the UK. Despite significant progress, therapies do not work in large numbers of patients, their efficacy wanes with time, and they leave people vulnerable to infection. I propose that understanding the complex interplay of immune cells in affected tissues will enable new treatments to be developed. My team and I study the development and behaviour of a type of white blood cell called a T cell. T cells are required for killing of infections and for development of cellular memory, for example following vaccination, but they can also induce profound damage to healthy tissue. This occurs for example if they are switched on in the wrong place, in response to the wrong trigger, or if they persist for too long following a productive response. In these situations, T cell behaviour is both directly and indirectly a cause of autoimmune disease. Therapies for such diseases often target the T cells themselves, their migration into affected organs or their products. However, many problems exist with the current therapies and much remains to be understood about how T cells trigger tissue damage and how they can be switched off. It is imperative that we develop new treatments which can be precisely targeted to only those T cells which are causing damage and only those present in the damaged tissue, leaving all others unaffected. To do this, we need to understand deeply how they develop, how they are triggered, and how they change throughout disease, and it is essential we do so using clinical samples donated from patients, to maximise the translational value of our research. I propose that a key trigger of these damaging T cells is the infiltration of another immune cell, the neutrophil. Neutrophils are the most abundant white blood cells in the circulation and move rapidly into damaged tissues in their millions. We know from our previous work that they interact closely with T cells, and they can drive T cells to the behaviour that causes autoimmune disease. We have only so far studied this in mice, or in dishes in the lab. Now I have designed an ambitious programme of work to understand how neutrophils affect T cells in real clinical samples from patients with Multiple Sclerosis or Crohn’s disease. The objectives of this work are to 1) understand for the first time precisely how these two cells interact; 2) determine how this differs between tissues (brain, intestine, lymph node, blood) and between diseases; and 3) identify key neutrophil actions which trigger damaging T cells. We aim to pinpoint a number of neutrophil products which drive T cell dysfunction, or identify specific neutrophil-responding pathways in the T cells themselves, to develop as novel therapeutic targets in future work. This work will be of interest to immunologists studying T cell differentiation and neutrophil biology, and will result in a new understanding of how these two immune cells interact in long-term diseases. It will develop large datasets of great value to the academic and clinical communities. We will also work closely with patients to develop accessible resources relating to our work.