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European Network linking informatics and genomics of helper T cells

Periodic Reporting for period 2 - ENLIGHT-TEN (European Network linking informatics and genomics of helper T cells)

Reporting period: 2017-10-01 to 2019-09-30

ENLIGHT-TEN was an ITN that provided cross-disciplinary training in T cell immunology and big data analysis and trained a new generation of researchers to exploit the power of emerging technological platforms to gain an in-depth knowledge of T cell differentiation and activation. This knowledge is critical to selectively manipulate T cell responses for therapeutic interventions in a wide-range of immune-mediated pathologies. The use of checkpoint inhibitors to increase anti-tumor responses has recently gained considerable attention, and suppressing T cell-mediated immune responses to ameliorate autoimmunity is an equally important goal.
One of the challenges created by the rapid implementation of next-generation sequencing technologies is the gulf between laboratories having expertise in T cell biology and those being equipped to handle big data. Thus, ENLIGHT-TEN trained a cohort of early-stage researchers (ESRs) to be comfortable in both areas: to have an in-depth understanding of T cell biology alongside the capacity to generate and process large data sets. ENLIGHT-TEN has developed a cross-disciplinary, high-quality educational programme to provide all its ESRs with specialist high-level research training, a broad scientific skill set and experience in both academic and industrial working environments.
The core of the training activities were the network-wide training modules. Four summer schools were carefully designed and enthusiastically executed by ENLIGHT-TEN. The 1st summer school “Basic Aspects of the Immune System“ was hosted in Turku (6th-9th June 2016). It introduced ESRs and external participants to various aspects of the immune system. In addition, an interactive workshop on the basics of disseminating EU projects was part of the summer school. To make the ESRs familiar with the Grant Agreement and the European Charter & Code for Researchers a quiz was developed. The 2nd summer school “Introduction to bioinformatic resources for immunologists” was hosted by ENLIGHT TEN partner EBI (12th-16th June, 2017). It provided participants with an overview of best-practice methods in applying bioinformatics approaches and enabled them to become confident users of their own and public domain data. The summer school was very successful and addressed an important training need, so that EBI continued to offer the newly developed course. The 3rd summer school “Translational research and medicines development” was hosted by BAYER in Berlin (16th-20th April 2018). The summer school introduced the participants to the knowledge, philosophy and tools needed in translational research and medicine development, empowering them to make a difference in translational medicine. A faculty of 13 high-profile professionals from industry, academia and biotech introduced the basics of the medicines development process including real-life case studies. The 4th summer school “How to succeed in finding and getting a job for biomedical researchers took place at the Babraham Institute (28th-30th January 2019). The course, run by a panel of professionals working in pharma, SMEs, academia and regulatory agencies, introduced the ESRs to different strategies of finding a job and included feedback on their CVs from experienced recruiters. Another important cornerstone of the training were strategically relevant secondments to other network participants.
A highlight of the project was the International Symposium “ENLIGHT-TENed by big data: advancing T cell immunology”, which took place on 2nd September 2018 as a satellite meeting of ECI2018, the biggest immunology conference in Europe. As part of the training programme, the ESRs were responsible for the organisation of this event. They successfully attracted high-profile speakers and more than 200 registrants. The International Symposium was flanked by an art exhibition “Art Enlightening Immunology” to communicate complex scientific results of ENLIGHT-TEN to the general public. The exhibition was hosted in the heart of Amsterdam by the Waag Society. Three renowned artists, Marta de Menezes, Herwig Turk and Andrew Carnie, transformed immunological concepts into art works and stimulated lively discussions, attracting over 450 visitors. A report on the symposium and the art exhibition appeared in the “European Journal of Immunology” (https://doi.org/10.1002/eji.201870145).
WP1 aimed at identifying critical molecular players involved in the development and differentiation of specific CD4+ T cell subsets. All objectives were comprehensively achieved, with global omics data collected using bulk and single-cell methods for many T cell subsets in lymphoid and non-lymphoid tissues. Coupled with knockdowns and computational analysis methods these results revealed new insights into the transcriptional regulation of CD4+ T cell subsets during differentiation and migration. WP2 studied environmental and molecular factors controlling the activity and reprogramming of differentiated T cells, a process having major implications for the functioning of the immune system in healthy individuals and during immunopathologies. Epigenetic signatures and metabolic pathways controlling the activity and reprogramming of helper T cell subsets were analysed. New candidate molecules and pathways identified as critical players in plasticity were knocked down or over-expressed in mature T cells to reveal and validate their specific function in vitro in human cells, and in vivo in mice. WP3 analysed the differentiation states of T cells responsible for causing immuno-pathologies. The work exploited mouse models and patient samples with a focus on autoimmune diseases such as type 1 diabetes and allergy. Effector T cells and Tregs isolated from pathogenic settings were analysed using a broad range of methodologies. The role of specific genes and environmental factors in controlling the differentiation of T cells into pathogenic phenotypes was assessed. Newly identified target genes were knocked down in T cell subsets to assess their importance for the pathophysiology of disease. These studies provide the basis for identification of novel biomarkers and therapeutic targets of autoimmune and atopic diseases. The work has also revealed a new connection between the CD28 pathway, Tfh differentiation and type 1 diabetes development. WP4 analysed genome-wide omics data from various T cell subsets generated in WP1-3, and developed novel bioinformatic algorithms for their integration and interpretation, including tools for transcription factor binding site prediction and multi-level biomarker signature detection. Highly-qualified bioinformaticians from the academic and private sector worked together to unify data collection methodologies and bioinformatic analyses in order to maximise cross-network and cross-project comparability. Computational predictions were refined and validated in functional in vitro and in vivo experiments in order to generate a holistic view of differentiation and plasticity of CD4+ T cell subsets and identify T cell-related molecular signatures as novel biomarkers for autoimmune diseases.