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

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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.