The role of type 2 innate lymphoid cells in autoimmune islet infiltration and diabetes

Type 1 diabetes is an increasing problem in the UK and worldwide, with rising numbers of people being affected year on year. The underlying problem is that the immune system attacks and destroys the cells that make insulin in the pancreas. We know that a type of immune cell called a T-cell is responsible for driving the process, however it does not work alone: coordinated interaction between a number of different cell types is required. Understanding the contribution of these different cell types to the disease process is vital for us to design ways to interfere with the immune-mediated attack in an informed way.

While analysing the immune cells infiltrating the pancreas in autoimmune diabetes, we recently discovered a population that has not been reported here before. These so called "Innate Lymphoid Cells" or ILC are relative newcomers to the field but have generated lots of excitement over the last few years. They are rare cells, but appear capable of profoundly influencing immune responses - i.e. they punch above their weight. It has been shown that they can change the way T-cells behave, instructing them to secrete different products and alter the type of immune response that is occurring. We have very recent data showing that they can alter whether T-cells secrete something called IL-21 which we know is linked to the development of type 1 diabetes. It is therefore possible that ILC play a key role in determining whether a destructive immune response against the pancreas is mounted.

At present nothing is known about the role of ILC in type 1 diabetes since the area is completely uninvestigated. Our proposed experiments will define how ILC affect T-cells during the initiation of an immune response in the pancreas, and in turn how the T-cells influence the ILCs themselves. We will use clues from our preliminary data, and the latest discoveries from the ILC field, to ask questions about whether ILC respond to dying pancreas cells or interact with nervous system components. By collaborating with leading experts in ILC biology, we will perform experiments to directly test whether ILC influence diabetes induction or progression.

Importantly, some of the treatments being developed for autoimmune diseases like type 1 diabetes are likely to act on ILC as well as T-cells. It is therefore vital to understand whether ILC play a positive or negative role in disease development so that these drugs can be used correctly.

Collectively this project will build on exciting new data from our group to define the role of a new player in the immune-mediated attack on the pancreas.

In recent years it has become apparent that innate lymphoid cells (ILC) can potently influence immune responses. They can directly elicit innate effector functions and can also shape the nature of adaptive immune responses. We have identified a population of type 2 ILC (ILC2) in the pancreas of mice developing autoimmune diabetes. We hypothesise that the presence of ILC2 at this site will influence the complex cellular cross-talk involved in pancreatic beta-cell destruction. In support of this, our preliminary data show that pancreatic ILC2 reprogramme their effector functions in response to islet-infiltrating T cells, and that ILC2 products can alter T cell production of diabetes-relevant cytokines.

In this project we will dissect how the bi-directional interplay between local ILC2 and islet-specific T cells influences the emerging autoimmune response, using state-of-the-art tools to unpick the molecular and cellular pathways responsible. We will define precisely how ILC2 change following T cell invasion of the pancreatic islets and unravel the downstream consequences of this for the immune response. Stimulated by our preliminary transcriptional analysis, we will test whether ILC2 can sense dying beta-cells and examine ILC/neuronal cross-talk. Finally we will use new models to test the contribution of ILC2 to diabetes development, and establish whether circulating ILC populations are altered in type 1 diabetes patients.

These experiments have direct implications for our understanding of disease pathogenesis in type 1 diabetes and will fill a significant knowledge gap in the field. Notably many of the T-cell directed immunotherapies being trialed in diabetes would also be predicted to affect ILC2, so establishing whether these cells promote or inhibit disease is of high importance. Insights gained from the project may also be of broader significance to autoimmune tissue infiltration in other disease settings.

Benefits to Industry
The development of novel therapies by the pharmaceutical industry entails a significant investment of time and money. The success of such therapies is contingent on the quality of the information that informs decisions on what to target and how to target it. Strategies to achieve immunomodulation in the setting of type 1 diabetes are based on our current understanding of the cell types that participate in this deleterious immune response. Our discovery that a previously unrecognized cell type is present at the site of the autoimmune attack, and responds to the presence of islet-infiltrating T cells, could significantly alter our approaches to future immunotherapy. The knowledge that particular therapies would target pancreatic ILC2 as well as T cells during T1D development has major implications for how that therapy would alter the immune response. Defining the impact of ILC2 on T1D development would allow informed predictions of how stimulating, inhibiting or depleting this subset would alter the disease course. Therefore the insights generated during this project would be of high value to the pharmaceutical industry in guiding drug development and selecting relevant indications.

Benefits to Patients
This project will improve our understanding of the immune response that drives the development of type 1 diabetes. A detailed knowledge of which cell types and molecular pathways are involved in disease development will ultimately permit the design of therapeutic strategies to counteract this destructive immune response. At present, when drugs are selected to be trialled in T1D there is no consideration of their impact on pancreatic ILC2 since the participation of this cell type in islet inflammation is not appreciated. Defining the role of these cells in T1D would help us to better predict the safety profile of drugs expected to affect them, thereby protecting patients who engage in clinical trials.

Training and career development
The work will support the career development of postdoctoral and technical scientists, allowing them training in the analysis of a newly recognised cell type in the setting of an important immune-mediated disease. The collaborative aspects of the work will give them access to different research environments and allow them to enhance their skill sets as well as disseminate understanding from our work.