Determining a novel pathway that controls TGF-beta activation in the immune system.

The immune system must be rapidly mobilised to eliminate infection, but be tightly regulated to prevent self-harmful immune responses. When this regulation breaks down, severe health problems can occur in animals and humans such as uncontrolled infection or autoimmune disorders (where the immune system attacks the body's own tissues and organs). As regulation of the immune system involves many different cells communicating with each other, it is essential that we understand the signals and mechanisms involved in this communication to understand how the immune system maintains health.

An important signal in the immune system is provided by a protein called transforming growth factor-beta (TGF-beta). TGF-beta acts as an anti-inflammatory molecule, important in regulating potentially harmful immune responses. However, in some scenarios TGF-beta is capable of promoting harmful immune responses. Hence, understanding how this key molecule is controlled is essential in understanding how the immune system is properly regulated.

Our recent work has highlighted an important pathway that is crucial in controlling the actions of TGF-beta in the immune system. Thus, we have shown that a receptor called integrin alphav beta8, when present on cells of the immune system called dendritic cells, activates TGF-beta to suppress harmful immune responses in the intestine. Additionally, this pathway is important in promoting harmful immune responses during models of autoimmunity and infection. Hence, integrin alphav beta8 is vital in controlling diverse immune responses. However, at present we know very little about how the integrin alphav beta8-TGF-beta pathway controls different types of immune response.

The aim of this proposal is to identify a completely new way by which integrin alphav beta8 regulates immune responses. It was previously thought that this molecule is found on the surface of cells. However, we now find that the integrin is secreted from immune cells on so-called 'extracellular vesicles', which are known to be capable of promoting communication with other cells of the immune system. Our proposal will define the importance of this pathway, and how it is controlled. Such work will allow us to better understand the biological mechanisms that regulate the immune system to maintain health.

The immune system must rapidly respond to pathogens, but during health be tightly regulated to prevent harmful immune responses that can lead to autoimmune disease. A key molecule in regulating immunity is the cytokine TGF-beta. Mice lacking the predominate isoform of TGF-beta in the immune system, TGF-beta1, die from inflammatory disease, highlighting the importance of this molecule in maintaining health. However, TGF-beta can also have important pro-inflammatory functions in some autoimmune diseases, highlighting a diverse role for TGF-beta in regulation of immunity. Hence, understanding how TGF-beta function is controlled is key to understanding how the immune system is regulated.

TGF-beta is produced by many cell types, but always as a latent precursor protein that must be activated in order to bind to its receptor and signal. Our recent work has highlighted an important molecule in regulating TGF-beta activity in the immune system. Hence integrin alphav beta8, expressed by antigen-presenting dendritic cells of the immune system, is critical in maintaining immune homeostasis, and also in the promotion of certain autoimmune diseases and infections. However, at present we have little insight into the pathways that control how integrin alphav beta8 activates TGF-beta during the regulation of immune responses.

Our proposal aims to uncover a novel mechanism by which integrin alphav beta8 regulates TGF-beta to control immunity. Our preliminary data suggest that the integrin, which is generally considered a cell surface molecule, is secreted by dendritic cells on the surface of extracellular vesicles, and that these vesicles can promote TGF-beta activation. Our proposal will determine the functional importance of this pathway in regulation of T cell responses, and the molecular mechanisms that regulate the pathway. Our work therefore aims to define an important novel mechanism that can regulate the immune system required to maintain health.

Disorders of the immune system, ranging from allergic reactions to severe infections and autoimmune disease, are a major health problem in the UK, placing an increasing burden on health care resources. In order to determine how our immune system maintains health, it is essential that the underlying biological mechanisms that regulate immune responses are understood. Our project will have important impact in this area by identifying and characterising important cellular and molecular mechanisms that control how immune cells communicate. Specifically, we will identify a new way by which the multi-functional cytokine TGF-beta is activated by the integrin receptor alphav beta8, via secretion of the receptor by cells on vesicles, and how this is important in regulating immune responses. The work will therefore be of potential benefit to a wide range of people.

Discoveries made during our proposal will be of interest and importance to the large field of clinical and non-clinical researchers who study the basic biology behind the regulation of immune responses. Given the broad role of TGF-beta in regulating many different aspects of the immune response, our findings will inform the research of researchers from a diverse range of immunological backgrounds. Additionally, given the important function of TGF-beta in cells outside the immune system, defining mechanisms that control TGF-beta activity will be pertinent to cell biologists interested in broader aspects of cell biology, ranging from researchers interested in the basics of cell behaviour (migration, differentiation, apoptosis) to researchers interested in the cell biology of diseases such as cancer and fibrosis (in which TGF-beta has been implicated to play important roles). Other researchers will therefore benefit from our work by providing novel insights to inform their own research questions and direction.

Additionally, given that the molecular pathway we intend to study controls activation of TGF-beta, a molecule that controls a wide range of cellular functions, our work is likely to be of much broader interest to the drug discovery industry. Indeed, TGF-beta is already a therapeutic target by a number of companies for treatment of several disorders. Hence, mechanistic insights into how this molecule is controlled is likely to be of great potential benefit and interest to the drug discovery industry, by identifying novel components of the pathway to target. In the longer term, these benefits to industry will hopefully lead to benefits for the wider public, via the production of novel drugs to promote health.

In addition to potential benefits via the drug discovery industry, our proposal will aim to achieve greater immediate impact with the general public by using our research as a basis for a range of public engagement events. These events will benefit the public by increasing awareness of how the immune system works, the importance of immunity in the maintenance of health, and the ways scientists carry out basic research with a view to better understanding complex systems.

Our work will also benefit the research team of Travis, Davis, Woodman and the post-doctoral research associate Kelly. Given the multi-disciplinary nature of the work, encompassing aspects of immunology, cell biology and biochemistry, Kelly will receive extensive training in wide-ranging areas of scientific research. Additionally, the project will benefit Travis, Davis and Woodman by extending their knowledge breadth into new scientific areas, which is becoming which is becoming more essential in tackling modern day biological problems.