Specific informations on research projects

In order to better understand how T cells make fate decisions in health and disease, early stage researchers (ESRs) will work on research projects that are embedded in four scientific work packages (WPs).

• WP 1: Early stages in the career of a T cell

In WP1, we aim to identify critical molecular players involved in the development and differentiation of specific CD4⁺ T cell subsets. By using global strategies and methods (e.g. multi-colour flow cytometry, RNA-seq, single-cell RNA-seq, small ncRNA-seq, Bi-seq, ChIP-seq, in silico prediction of transcription factor target genes), candidate genes involved in the CD4/CD8 T cell fate choice during thymic development will be analysed, including molecular factors determining thymic Treg development. Regulatory molecules controlling the switch of naive CD4⁺ T cells towards different types of helper T cell subsets (including induced Tregs) will also be identified. Novel candidate genes will be knocked down in thymocytes and mature T cells to reveal and validate their specific function in vitro in human and mouse cells, and in vivo in mice.

• WP 2: Plasticity and reprogramming of differentiated T cells

In WP2, we will study 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 (e.g. Th17 and Tfh cells) will be analysed. Similar strategies and methods as described in the first workpackage (e.g. multi-colour flow cytometry, RNA-seq, single-cell RNA-seq, Bi-seq, ChIP-seq, mass spectrometry, in silico prediction of transcription factor target genes, screening of small molecule libraries) and state-of-the-art promoter-capture HiC will be applied. New candidate molecules and pathways identified as critical players in T cell subset plasticity will be 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.

WP 3: Immunopathologies caused by dysregulated T cells

In WP3, we will analyse the differentiation states of T cells responsible for causing immunopathologies. The work will exploit mouse models and patient samples with a focus on autoimmune diseases (including type 1 diabetes and multiple sclerosis) and allergy. We will characterise T cells isolated from pathogenic settings using a broad range of methodologies (e.g. multi-parameter flow cytometry, single-cell RNA-seq). The role of specific genes and environmental factors in controlling the differentiation of T cells into pathogenic phenotypes, including Th17 and Tfh cells, will be assessed. We will also study how Treg populations develop and function in settings of immunopathology. Newly identified target genes will be knocked down in T cell subsets to assess their importance for the pathophysiology of disease. These studies will pave the way for identification of novel biomarkers and new therapeutic targets of autoimmune and atopic diseases.

• WP 4: -omics and bioinformatics

WP4 is the glue between all scientific work packages. Here, we will generate and analyse all genome-wide -omics data (e.g. RNA-seq, Bi-seq or ChIP-seq) of the whole consortium and develop novel bioinformatic algorithms for their integration and interpretation, including an in silico transcription factor binding site prediction tool and a tool for multi-level biomarker signature detection. Highly qualified bioinformaticians from the academic and private sector will work together to unify data collection methodologies and bioinformatic analyses in order to maximise cross-network and cross-project comparability. This step will be facilitated by the EMBL-EBI, which has strong expertise in protocol optimization and setting standards in international data sharing. Computational predictions will be refined and validated in functional in vitro and in vivo experiments in order to generate a novel and holistic view of differentiation and plasticity of CD4⁺ T cell subsets and to identify T cell related molecular signatures as novel biomarkers for autoimmune diseases.

Early stages in the career of a T cell

Plasticity and reprogramming of differentiated T cells

Immunopathologies caused by dysregulated T cells

-omics and bioinformatics

This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.: 675395

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