Regulation of the immune response: the role of integrin alphavbeta8 and TGF-beta in immune homeostasis and response to pathogens.

The immune system functions to detect and destroy harmful pathogens that enter the body. Upon infection, the immune system is rapidly activated, to ensure the threat is dealt with as quickly as possible. However, in healthy individuals it is vital that the immune system is kept in a resting state to prevent tissues of the body from being attacked; a process that results in debilitating autoimmune disease. A vital area of research is concerned with understanding the pathways and molecules that control the balance between a resting and active immune system. We have recently identified a vital pathway which prevents the immune system from attacking tissues of the body. When a protein molecule called integrin alphavbeta8 is not present on the dendritic cells of the immune system, severe autoimmune disease occurs. The work proposed here aims to study this pathway in more detail, looking at which specific types of cell in the immune system are important, and to determine what happens to this pathway during active immune responses to infection. Such work will provide important insights into how animals and humans successfully deal with infection, and how the immune system is tightly regulated to prevent autoimmune disease.

The immune system has evolved to protect the body from infection by quickly detecting and destroying harmful pathogens. However, in normal circumstances, it is vital that the immune system is kept in a resting state, to prevent harmful immune responses directed against self-tissues, leading to autoimmune disease. An important molecule in the regulation of immunity is the cytokine transforming growth factor-beta (TGF-beta). TGF-beta is an important anti-inflammatory cytokine, as shown by the TGF-beta1 knockout mouse, which dies from multi-organ autoimmune disease due to unregulated immune responses. TGF-beta is synthesized and secreted from cells as part of a latent protein complex, and needs to be activated to exert effects on TGF-beta receptor-expressing cells. Therefore, increasing our knowledge of how TGF-beta is activated in vivo will be vital in understanding how TGF-beta regulates the immune system. Our recent studies have uncovered a novel role for the integrin alphavbeta8 in activating TGF-beta in the adaptive immune system. Mice lacking integrin alphavbeta8 on antigen-presenting dendritic cells develop severe autoimmune disease, characterised by unregulated T-cell activation and severe colitis. This disease results from a reduced ability of dendritic cells to activate TGF-beta via integrin alphavbeta8. However, many crucial biological questions remain. Which types of dendritic cell are involved in this pathway? What is the role of this pathway at times of immune challenge? What happens to this pathway once the immune system has successfully eradicated an infection? This project will utilise conditional knockout mouse models to enhance our understanding of an important pathway in regulation of the immune system. Specifically, we will investigate the role of integrin-mediated TGF-beta activation in control of immune responses. This work will provide new insights into how the adaptive immune system is regulated at rest and in response to infection.