Signalling pathways and gene regulatory networks responsible for Th17 cell differentiation

Lead Research Organisation: MRC National Inst for Medical Research
Department Name: Division of Molecular Immunology

Abstract

Lymphocytes are central for the regulation of an immune response. CD4+ T lymphocytes can differentiate to functionally distinct subsets and classified based on their cytokine secretion profiles as well as other properties. Proper regulation and balance between various lymphocyte subsets is central for the appropriate function of the immune system and required e.g. for host defence against pathogens or cancer as well as protection from autoimmune diseases. Recently, a new effector CD4+ T cell subset Th17 was discovered and named according to the main cytokine they secrete, IL17. Besides being involved in host defence to extracellular pathogens, Th17 cells play a central role in the pathogenesis of inflammatory diseases in human and experimental mouse models. The recent discovery by the Stockinger group links the aryl hydrocarbon receptor, a transcription factor widely studied in the toxicology field, and the Th17 system, which provides new hypotheses on the potential mechanisms underlying the well-established connection between the environmental factors and autoimmune diseases. The cellular response to an external stimulus is mediated through a series of overlapping networks that include the signalling network, the epigenetic and transcription factor control mechanisms at genome level, and the gene regulatory. In this project we will study these control mechanisms during the differentiation of Th17 cells by combining genome-wide experimental and computational approaches. We expect that our project results in the identification of the key regulatory components of each of the networks involved, as well as provide insights into the nature of molecular interactions between them. Such regulatory hubs, or the pathways that they participate in, provide targets for rational chemotherapy either for the immune-mediated diseases described above, or for enhancing protective immunity against infectious agents. Our multidisciplinary consortium provides cutting-edge complementary expertise to achieve the goals.

Technical Summary

Lymphocytes are central for the regulation of an immune response. CD4+ T lymphocytes can differentiate to functionally distinct subsets and classified based on their cytokine secretion profiles as well as other properties. Proper regulation and balance between various lymphocyte subsets is central for the appropriate function of the immune system and required e.g. for host defence against pathogens or cancer as well as protection from autoimmune diseases. Recently, a new effector CD4+ T cell subset Th17 was discovered and named according to the main cytokine they secrete, IL17. Besides being involved in host defence to extracellular pathogens, Th17 cells play a central role in the pathogenesis of inflammatory diseases in human and experimental mouse models. The recent discovery by the Stockinger group links the aryl hydrocarbon receptor, a transcription factor widely studied in the toxicology field, and the Th17 system, which provides new hypotheses on the potential mechanisms underlying the well-established connection between the environmental factors and autoimmune diseases. The cellular response to an external stimulus is mediated through a series of overlapping networks that include the signalling network, the epigenetic and transcription factor control mechanisms at genome level, and the gene regulatory. In this project we will study these control mechanisms during the differentiation of Th17 cells by combining genome-wide experimental and computational approaches. We expect that our project results in the identification of the key regulatory components of each of the networks involved, as well as provide insights into the nature of molecular interactions between them. Such regulatory hubs, or the pathways that they participate in, provide targets for rational chemotherapy either for the immune-mediated diseases described above, or for enhancing protective immunity against infectious agents. Our multidisciplinary consortium provides cutting-edge complement

Planned Impact

This proposal by a multidisciplinary international consortium provides cutting-edge complementary expertise for achievement of the goals. The central aspect is comprehensive high throughput profiling of T cell differentiation and its regulation. The T cell subset we are focusing on has a profound role in many autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, myocarditis and other inflammatory diseases. On the other hand Th17 cells have important beneficial roles in recruiting innate immune components in infection as well as maintaining barrier function at mucosal sites. It is therefore to be expected that a fundamental analysis of the factors that drive the differentiation and regulation of this T cell subset will impact substantially on eventual development of therapeutic regimes that will allow rational manipulation of the immune response. Thorough scientific knowledge generation to underpin future therapeutic exploitation is a prerequisite for any impact in the academic research community, the medical community and private commercial sector. Communications and engagement: The initial beneficiaries will be the wider research community as our findings generate new scientific knowledge and scientific advancement. It is difficult to predict how and if public policy making will be affected, but if indeed our results open up new possibilities for therapeutic developments we would anticipate clinicians as well as the private commercial sector to be involved in developing reagents that could be integrated into clinical trials. Our research will be extensively disseminated to the medical community in participating countries and globally by research papers in medical journals and presentations of the data in national and international meetings. If any practices that could be changed to promote health and minimise risks are identified, the authorities will be notified immediately. The project will have its own website to allow both interactive exchange of data within the consortium which would be restricted access as well as presentation of the project, its partners and results as open access. Whenever appropriate we will consider other forms of dissemination including contacts with media, TV, radio and other publications with a specific interest in the project. There are various forms of public engagement that could be employed. NIMR has an active schools programme which aims to foster and stimulate interest in science and research among young people. Each year a Schools day is held where students from local schools visit the Institute for an afternoon. There is also an annual essay competition for sixth formers in local schools with a first prize of £100 and the opportunity to visit scientists in their laboratories. Furthermore, since 2003 NIMR has hosted an annual meeting for the North London region of the University of the Third Age (U3A), with talks by members of staff which has been enthusiastically attended by around 150 U3A members. Collaboration and exchange of knowledge: The multidisciplinary interaction of partners from different European countries will foster exchange of knowledge within Europe. Consortium partners will organize project meetings, which will be hosted each year by a different partner. They will provide the opportunity for young scientists to practise their presentation skills and give them networking opportunities. We may also organise project meetings through skype to reduce travel costs if needed. There will also be the possibility for short term exchange visits for postgraduate or postdoctoral scientists to allow training and transfer of technology between participating labs. Exploitation and application: The intellectual property rights will be carefully considered and secured and the Technology Transfer section of each participating partner has been notified to the potential. The project may have potential economic value in the longterm and patent inventions may be m

Publications

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Description This was a collaborative EU Framework 7 grant coordinated by the Institute for Biotechnology in Turku with participation of bioinformatics groups from the Netherlands and Finland. The aim was to obtain a detailed kinetic comparison of transcriptional changes comparing mouse and human Th17 cells.

Workpackage 1 with 4 milestones was completed according to schedule and NIMR contributed the samples of mouse Th17 cells generated by culture in four different conditions and comparing also cells expression different affinities of the aryl hydrocarbon receptor that is functionally important in Th17 cells. 312 RNA samples were subjected to Illumina deep sequencing. The two bioinformatics labs are still in the process of finalising the comparative analysis, but a study on detailed kinetic changes of gene expression profiling of human Th17 cell differentiation was published (Tuomela et al, Blood. 2012 Jun 7;119(23):e151-60. Epub 2012 Apr 27). This study led to identification of over 1000 genes differentially expressed during early human Th17 differentiation. Within these genes, many of them are new players identified from our study. With publication of this study, the dataset is now publicly available which provides the starting point for constructing the gene regulatory network and identifying new candidates possibly regulating the Th17 differentiation in human not only for us but also benefit for all researchers interested in this field.
Exploitation Route Th17 cells are major contributors to inflammatory pathologies in human diseases such as rheumatoid arthritis, multiple sclerosis or psoriasis. Understanding the developmental processes for generation of these cells as well as the potential contribution of environmental factors that act via the aryl hydrocarbon receptor might open novel windows for development of therapeutics to intervene in the development of pathogenic Th17 cells.