Award details

Integrin-mediated regulation of NK cell motility and function

Reference	BB/M023540/1
Principal Investigator / Supervisor	Dr Janine Coombes
Co-Investigators / Co-Supervisors
Institution	University of Liverpool
Department	Institute of Infection and Global Health
Funding type	Research
Value (£)	471,399
Status	Completed
Type	Research Grant
Start date	11/01/2016
End date	31/12/2019
Duration	48 months

Abstract

NK cells maintain normal mammalian physiology by regulating tissue inflammation, contributing to successful pregnancies, and providing surveillance against malignant cells and pathogens. Dysregulation of NK cell function can lead to uncontrolled growth of pathogens or tumours, inflammation or miscarriage. Consequently, manipulation of endogenous NK cells, or adoptive NK cell immunotherapy, are attractive approaches to ameliorating disease. A major limiting factor in our ability to deliver successful NK cell based therapies is a lack of understanding of the factors regulating migration of NK cells within tissues. Intra-vital imaging studies have focused our attention on the role of the tissue environment in regulating immune cell motility and function. Using two-photon microscopy, we have shown that NK cell migration in infected lymph nodes is regulated by interactions between the integrin, a2b1, and collagen fibres. This finding offers a potential candidate for therapeutic modulation of NK cells, but we do not yet know how a2b1 activity is regulated, whether a2b1 is critical for NK cell function, or whether other integrins play significant roles in regulating NK cell motility in vivo. Interestingly, we have also shown that NK cells directly invaded by the intracellular parasite, Toxoplasma gondii, behave differently to rest of the NK cell population. Invaded NK cells do not interact with collagen fibres, and instead display a "hypermotility" phenotype indicative of altered integrin activity. This provides a useful tool to understand the molecular pathways regulating NK cell migration. We will use state-of the art imaging techniques, combined with novel proteomic methodologies, to provide a comprehensive picture of the molecular pathways underpinning integrin-mediated regulation of NK cell migration and function in tissues. This will reveal novel candidates for the development of therapeutic strategies for optimising NK cell activity in health and disease.

Summary

Natural Killer (NK) cells are cells of the immune system that play a crucial role in eliminating infected or cancerous "target" cells from the body. However, NK cells sometimes fail to control tumours and have been implicated in recurrent miscarriage and the development of inflammatory diseases. Consequently, manipulating the function of a patient's NK cells, or giving them extra NK cells that function properly, are attractive approaches to ameliorating disease. To achieve this, it is important that we understand the factors that determine whether NK cells are protective, destructive, or ineffective. We believe that a key factor regulating NK cell function is their ability to migrate through, and localise correctly within complex tissues. For example, NK cells may fail to properly control tumour growth when they become stuck in the dense tissue deposited around tumour cells, preventing them from directly interacting with, and killing, the tumour cells. If we can understand the factors regulating NK cell migration through tissues, we can alter NK cell function to prevent or cure disease. However, mammalian tissues are highly complex, and our understanding of the signals that control the movement of NK cells is currently very limited. Two-photon microscopy is an imaging technique that allows us to look deep inside living tissues and observe the behaviour of immune cells in real time. Using this technique, we have shown that NK cells use a specific protein on the cell surface, called a2b1 integrin, to stick to bundles of collagen in infected tissues. This controls the speed of NK cell migration, and may either ensure that NK cells are retained where they are needed, or may prevent NK cells from seeking out and killing "target" cells. While this finding offers a potential candidate for therapeutic modulation of NK cell behaviour and function, we do not yet know how a2b1 activity is regulated on NK cells, or whether a2b1 is critical for NK cell function. In this project, we will use two-photon microscopy, together with genetically engineered mouse models, to address these points. Infectious agents can manipulate cells of the immune system for their own benefit, and understanding how they do this can give us important information about how the immune system normally works. Toxoplasma gondii is a common parasite of humans and other warm-blooded animals that forms cysts in the brain. T. gondii can invade immune cells, alter the way they migrate, and use them to travel around the body. My work suggests that the parasite is capable of detaching NK cells from the collagen, allowing them to move faster and further. This provides a useful tool to understand how a2b1 activity is regulated on NK cells, and the molecular pathways regulating NK cell migration. In this project, we will use innovative proteomics techniques to determine how T. gondii alters a2b1-mediated interactions between NK cells and tissues. Together with our imaging data, this will allow us to uncover the molecular pathways underpinning NK cell migration and function in tissues. Increased understanding of the molecular pathways regulating NK cell migration and function will allow us to identify candidates that could be targeted therapeutically to optimise NK cell activity and ameliorate disease.

Impact Summary

This proposal will provide new understanding of the mechanisms underpinning NK cell function in complex tissue environments. The major impact of the research will be in the following key areas: UK academic research community: The UK has a highly active community of researchers working on fundamental NK cell biology, and the role of NK cells in cancer, infection, pregnancy, asthma, autoimmunity and ageing. Our findings will be of considerable interest in providing (1) crucial information about how NK cell activity is regulated in complex tissues, and (2) improved methodologies for the study of NK cell dynamics across a range of tissues and disease models. The direct outcomes of this proposal, and collaborative relationships built as a result, will allow us to understand how NK cells can be managed therapeutically to prevent and ameliorate disease (see academic beneficiaries). Our work will also further the development of key methodologies and tools for applying two-photon microscopy and proteomics to the study of host-pathogen interactions. This will benefit the large community of scientists at UoL working on infectious diseases of livestock and humans, and the wider UK research community. Training: This project, and the longer-term research program that it will help to establish, will support training of the next generation of UK scientists. The PDRA, in addition to the PhD and project students they help to supervise, will gain core skills in state-of-the-art imaging and proteomics techniques, specialist knowledge in NK cell biology, and transferrable skills in project management, communication and public engagement. This will contribute to the UK knowledge economy. UK biotechnology and pharmaceutical industries: The identification of specific pathways regulating NK cell migration and function in tissues will be of considerable interest to the UK biotechnology and pharmaceutical industries. The targets identified through our research can be exploited to design new drugs to modulate endogenous NK cell activity, or to genetically modify in vitro expanded NK cells for adoptive immunotherapy. For example, Novartis and Adaptimmune are currently interested in developing adoptive immunotherapy for cancer. This type of activity has knock-on effects on the UK economy in terms of the manufacture of new drugs, and the creation of jobs for highly skilled researchers. Health and wellbeing of the UK population: The economic and social burden of chronic disease is increasing as the population ages and becomes more susceptible to cancer, infection and autoimmunity. NK cells play important roles in all of these conditions, and changes occur in NK cell phenotype and function in the elderly. Our research will identify new ways of supporting healthy immune function, helping more patients with cancer or inflammatory disease to live healthier and more productive lives. Animal health industry: Our work will contribute to our understanding of how T. gondii spreads through the host, revealing targets for novel drugs and vaccines that can be exploited by the UK animal health industry. For example, Moredun Scientific and MSD-Animal Health have particular interests in T. gondii infection models and vaccines, respectively. UK farmers: The UK sheep industry loses over half a million lambs each year to Toxoplasmosis, at a cost of £12-24 million. Our results will identify new ways of targeting the spread of parasites, and suggest new candidates that be targeted by vaccines. This could be used to prevent trans-placental transmission, and reduce tissue cyst burden, alleviating the economic impact of T. gondii-induced abortion in sheep, and reducing transmission to humans through consumption of infected meat. Engagement with the public: The images and movies generated over the course of the project will provide an excellent way to engage the UK public and inform them about the societal benefits of the fundamental biological research.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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