Signatures microARNs de la réponse lymphocytaire T CD4+ modulée par l’interféron de type I

 

Responsable du Stage : Frédérique MICHEL, HDR, DR-IP

Tél 01 45 68 86 38, Fax : 01 40 61 32 04

Mail : frederique.michel@pasteur.fr

 

Résumé du Projet de Stage 

We study the immunomodulatory activity of type I interferon family (IFNa/b) on the human CD4+ T cell response in healthy donors and in a pathologic context with multiple sclerosis (MS) patients. This chronic autoimmune and inflammatory disease targets the central nervous system and leads to axonal demyelination and neurodegeneration, with gradual physical and cognitive disabilities. The relapsing-remitting disease (RRMS) is the most common form that can be treated by IFNb as a first-line therapy. However, the disease mainly evolves in time towards a secondary progressive form. In this context, there is a need for prognostic biomarkers of disease severity and progression.

Based on RNA-seq data and other data obtained with the Nanostring methodology, we have identified microRNAs (miRNAs) whose the level of expression is modulated by IFNb in activated CD4+ T cells of healthy donors. MiRNAs are small non-coding RNAs that bind to the 3’ untranslated region of messenger RNAs, causing their degradation and/or reduced translation. They play a critical role in the post-transcriptional regulation of genes that are involved in T cell differentiation. Moreover, their expression and activity differ according to the immune cell type and activation context.

The objectives of the project are: 1- to select IFN-modulated miRNAs of interest based on our previous data, bibliography and computational prediction. 2- to confirm the IFN-dependent modulation of the miRNAs by RT-qPCR with miRNA-specific primers in CD4+ T cells of additional healthy donors. 2- to study the functional impact of some miRNAs in the modulation of the CD4+ T cell response using a T cell line model and primary CD4+ T cells. 3- to investigate if some miRNAs may help to determine a molecular signature of immune cell subsets that play a pathogenic role in the MS disease. For that, distinct CD4+ T cells subsets will be sorted by flow cytometry from PBMCs of healthy donors and RRMS patients.

Références:

– Devi-Marulkar P, Moraes-Cabe C, Campagne P, Corre B, Meghraoui-Kheddar A, Bondet V, Llibre A, Duffy D, Maillart E, Papeix C, Pellegrini S, Michel F. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment. Front Immunol. 2021. doi: 10.3389/fimmu.2021.628375.

– Rubino E, Cruciani M, Tchitchek N, Le Tortorec A, Rolland AD, Veli Ö, Vallet L, Gaggi G, Michel F, Dejucq-Rainsford N, Pellegrini S. Human Ubiquitin-Specific Peptidase 18 Is Regulated by microRNAs via the 3’Untranslated Region, A Sequence Duplicated in Long Intergenic Non-coding RNA Genes Residing in chr22q11.21. Front Genet. 2021 doi: 10.3389/fgene.2020.627007.

-Li Z, Rotival M, Patin E, Michel F, Pellegrini S. 2020. Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage. PLoS ONE.15(1):e0225289. Doi: 10.1371/journal.pone.0225289

– U. Govender, B. Corre, Y. Bourdache, S. Pellegrini and F. Michel. 2017. Type I interferon-enhanced IL-10 expression in human CD4 T cells is regulated by STAT3, STAT2, and BATF transcription factors. J. Leukoc. Biol. Doi :10.1189/jlb.2A0416-187RR

– B. Corre, J. Perrier, M. El Khouri, S. Cerboni, S. Pellegrini and F. Michel. 2013. Type I interferon potentiates T-cell receptor mediated induction of IL-10-producing CD4⁺ T cells. Eur. J. Immunol., 43(10):2730-40.

– Z. Li, M. Gakovic, J. Ragimbeau, M-L Eloranta, L Rönnblom, F Michel and S Pellegrini. 2013. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J. Immunol., 190(5):2335-44.

M2-stage 2021-22, Paris 7-050821

 

Intitulé de l’Unité : Institut de Chimie Physique UMR8000 CNRS Université Paris Saclay

Intitulé de l’Equipe : Activation et Fonction lymphocytaire

Nom du Responsable de l’Unité : Sandra Pellegrini

Nom du Responsable de l’Équipe : Frédérique MICHEL

Adresse : Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris