Mots-Clés

Systems immunology T-cell receptor, TCR repertoire dynamics

Description

Project Title: Deciphering the dynamics of the human T-cell receptor repertoire

Summary of the lab’s interests: The i3 laboratory is interested in systems immunology approaches to identify new biomarkers for diagnosis and therapy with a particular focus on Treg biology and autoimmune disorders (AD). One of the unique expertise of the laboratory consists in identifying antigen-specific T cells through the analysis of T cell receptor repertoire using deep sequencing.

Summary of the proposed project: The mammalian adaptive response is mediated in part by T lymphocytes. These cells can recognize through their T-cell receptors (TCRs), antigens embedded by the major histocompatibility complex (MHC) and induce a cell-mediated response. They express a highly diversified set of TCRs that are assembled in the thymus during T-cell development through a somatic rearrangement process called V(D)J recombination. This process is estimated to give rise to a repertoire with a maximum diversity of 1019 different TCRs (Dupic et al. 2019). Fortunately, the emergence of NGS technologies in the last decade now allows the generation of massive amounts of data and the development of powerful analytical tools for comprehensive profiling of the TCR repertoire (Six et al. 2013; Barennes et al. 2021).

 The  TCR  repertoire is dynamic and constantly evolving within space and time:  space,  in that T-cells, are originally produced in the thymus then migrate to the periphery where they circulate between the lymph and blood,  encounter their cognate antigen and differentiate in different compartments and tissues; and time in that the response can be brief or long-lived. Deciphering an individual’s immune history, in search for example of previous infections, would call for the study of memory T-cell repertoires,  whereas looking into naïve cells would give insight into the reservoir of available specificities capable of responding to new challenges.

The M2 internship project will thus aim at carrying out an in-depth study of the human TCR repertoire (i) during T-cell development and selection in the thymus, (ii) by following its dynamics in the periphery, and (iii) according to age and sex. We have already collected 1000+ samples from humans covering different cell subsets including cytotoxic CD8+, conventional CD4+, and regulatory T cells under different activation states, from the thymus and various peripheral sites. The careful study of this large data collection at every aspect of the TCR repertoire will allow a deeper understanding of its dynamics and composition in different T cell subsets and anatomical locations in a physiological context.

Candidate profile: The expected candidate will have training in Immunology with a strong interest in Systems Biology and Bioinformatics. He/she will contribute to the modeling of this data collection using the available workflows developed in the laboratory as well as implementing new strategies. To do so, the candidate will benefit from the experience of bioinformaticians in the laboratory to develop his/her programming skills.

Lab description: The laboratory is offering a unique interdisciplinary environment, with biologists, immunologists, clinicians, computer scientists, and bioinformaticians. The candidate will be based in the i3 laboratory located on the Pitié‐Salpêtrière hospital campus in Paris (13ème).

Publication supervisors (related to the project): Barennes et al., Nature Biotechnology, 2021; Dupic et al., PLOS Computational Biology, 2019; Six et al., Frontiers in Immunology, 2013.