Mots-Clés
Autoimmune diseases
Single-cell RNA-seq
Spatial transcriptomics
Description
Project Title:
Multi-compartment single-cell multi-omics analysis in refractory celiac disease type 1
Scientific Context:
Autoimmune diseases often persist within specific tissues despite systemic immunosuppressive therapy. A major open question is whether this persistence simply reflects sustained immune activation, or whether it arises from genetic and functional evolution of immune clones that progressively alter their behavior and contribute to tissue damage or transformation.
Our research team explores this question in the context of autoimmune enteropathies, in particular refractory celiac disease (RCD), conditions where we have shown that tissue-resident T cells can acquire somatic alterations that favor their local persistence and disrupt intestinal homeostasis. These clonally expanded T cells may act as autonomous pathogenic units, sustaining inflammation and, in some cases, driving progression toward lymphoproliferative disorders.
RCD type 1 (RCD1) is defined by the persistence of intestinal symptoms and villous atrophy despite strict adherence to a gluten-free diet, in the absence of overt lymphoma. However, the boundary between RCD1 and overt malignant transformation remains poorly defined at the molecular level. A critical and unresolved question is whether clonally expanded T cells identified in the gut are strictly tissue-confined, or whether they disseminate to other anatomical compartments, and if so, whether they maintain the same transcriptional and functional identity across sites.
Project Description:
This internship is centered on the bioinformatic analysis of single-cell multi-omic data generated from patients diagnosed with RCD1 who presented with concomitant pulmonary involvement. Three distinct biological compartments were sampled: intestinal biopsy (duodenum), bronchoalveolar lavage (BAL), and peripheral blood. For each compartment, 5’ single-cell RNA-seq combined with V(D)J sequencing was performed, enabling simultaneous profiling of gene expression and T cell receptor (TCR) clonotype identity at single-cell resolution.
The central goal of the project is to characterize the pathogenic T cell clones across these three compartments, determine whether the same clones are shared, describe their transcriptional states in each tissue environment, and assess whether they display features associated with malignant or pre-malignant transformation.
To further anchor these findings in their tissue context, spatial transcriptomics will be performed on both intestinal and pulmonary biopsies. This additional data layer will provide information on the spatial organization of immune and epithelial cells within the tissue, enabling the localization of pathogenic clones and dysregulated transcriptional programs relative to tissue architecture.
Environment and Missions:
The intern will join a multidisciplinary team at the Imagine Institute (Paris), combining clinical expertise in gastroenterology and immunology with computational biology. They will benefit from close interactions with clinicians and wet-lab scientists, and will have access to dedicated computational resources.
Working primarily in R and/or Python, the intern’s missions will include:
• Quality control and integration of scRNA-seq and scTCR-seq data using state-of-the-art pipelines, to enable robust cross-compartment comparison
• Unsupervised clustering and cell type annotation, with a focus on T cell subpopulations, epithelial cells, and the identification of potential tumor cells displaying a pre-malignant phenotype
• Clonotype tracking across compartments: identification of shared TCR clonotypes between biopsy, BAL, and blood, and quantification of clonal expansion
• Transcriptional state analysis of expanded clones: gene expression profiling of dominant clones and identification of dysregulated pathways
• Spatial transcriptomics analysis and integration with single-cell data
Candidate Profile:
We are looking for a motivated M2 student with:
• Solid bioinformatics background (R and/or Python, command-line environment, HPC clusters)
• Basic knowledge of immunology, in particular T cell biology and/or TCR diversity, is a plus
• Good written and oral communication skills in English and/or French
• Curiosity, autonomy, and capacity to engage with the biological interpretation of results
Key references:
- Malamut G, Guégan N, … , Levescot A. Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease. Gastroenterology. 2026, doi: 10.1053/j.gastro.2026.03.025.
- Levescot A, Cerf-Bensussan N. Loss of tolerance to dietary proteins: From mouse models to human model diseases. Immunol Rev. 2024, doi: 10.1111/imr.13395.
- Levescot A, Malamut G, Cerf-Bensussan N. Immunopathogenesis and environmental triggers in coeliac disease. Gut.2022, doi: 10.1136/gutjnl-2021-326257.
- Cording S et al., Oncogenetic landscape of lymphomagenesis in coeliac disease. Gut. 2022, doi: 10.1136/gutjnl-2020-322935.
- Ettersperger J, et al., Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease. Immunity. 2016, doi: 10.1016/j.immuni.2016.07.018.