Role of MAIT cells in Interleukin-7 adjuvanted pulmonary vaccine
Responsable de l’encadrement : Anne Couedel-Courteille
Tél : 01 40 51 65 24 …… Fax : 01 40 51 65 35……… E-mail: email@example.com
Résumé du Projet de Stage
Despite tremendous work on vaccine development over the last decades, mucosal immune responses remain difficult to trigger and we still need to propose new vaccine strategies to specifically target mucosal immunity. The main objective of the project is to investigate the capacity of IL-7 to enhance mucosal immune responses to locally administered viral antigens. Indeed, we demonstrated that this cytokine is produced in infected mucosae and is able to trigger local expression of chemokines when administered either locally and systemically, leading to massive immune cell homing into targeted mucosae (Ponte et al, 2017). We thus hypothesize that locally delivered IL-7 can act as an efficient adjuvant to trigger mucosal immune responses to vaccines. Indeed, in macaques immunized vaginally, we showed that this strategy elicits strong mucosal immune responses (Logerot et al, 2021).
This project aims to explore how locally administered IL-7 predisposes mucosae to elicit efficient and long-lasting specific T and B mucosal immune responses against locally delivered antigens. We will focus on pulmonary mucosae, a major portal of entry for pathogens. Indeed, we already showed that mice intratrachealy administrated with IL-7 before delivery of a model antigen (Diphtheria Toxoid –DT) by the same route triggers a stronger and a more prolonged specific mucosal immune response than mice administered with antigen alone. Moreover, this procedure together with the administration of inactivated Inflenza virus (IAV) protects mice against IAV pathology. We now want to understand at a cellular level the mechanism by which IL-7 acts on pulmonary paremchyma to trigger immune cell recruitment early after deposition. In this context, we identified MAIT cells, among others immune cell subsets, to be increased upon IL-7 administration.
We now aim to explore the functions of these MAIT cells and their need in the IL-7 driven mucosal immune response. The aims for the Master 2:
- Better characterize these pulmonary MAIT cells increased upon intratracheal IL-7 administration in WT mice by spectral FACS analysis (tetramers, activation markers, markers of MAIT subsets) and RNA-seq after cell sorting.
- Localize them within the tissue combining immunochemistry to in situ hybridization (RNAscope) on pulmonary tissue of mice sacrificed at early time points post-IL7 administration with a special focus on organized lymphoid aggregates that form as early as 2 days post IL-7 within the pulmonary paremchyma
- In collaboration with Agnès Lehuen team at Institut Cochin, we will explore, in mice devoided of MAIT cells (MR1KO mice compared to their littermates MR1+/-), the requirement of MAIT cells in mounting a good immune response against DT.
This work will establish the impact of instillation of IL-7 into the lungs on MAIT cell biology and their role in the development of lung immunity following mucosal vaccination.
Dernières Publications en lien avec le projet :
- Logerot S, Figueiredo-Morgado S, Charmeteau-de-Muylder B, Sandouk A, Drillet-Dangeard A-S, Bomsel M, Bourgault-Villada I, Couedel-Courteille A, Cheynier R, Rancez M. IL-7-adjuvanted vaginal vaccine elicits strong mucosal immune responses in non-human primates. Front Immunol. 2021 doi:10.3389/fimmu.2021.614115
- Ponte R, Rancez M, Figueiredo-Morgado S, Dutrieux J, Fabre-Mersseman V, Charmeteau-de-Muylder B, Guilbert T, Routy JP, Cheynier R, Couëdel-Courteille A. Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing. Front Immunol. 2017. doi:10.3389/fimmu.2017.00588.
- 3. Rancez M, Couëdel-Courteille A, Cheynier R. Chemokines at mucosal barriers and their impact on HIV infection. Cytokine Growth Factor Rev. 2012 Jun 22. doi: 10.1016/j.cytogfr.2012.05.010
4.Toubal A, Nel I, Lotersztajn S, Lehuen A. Mucosal-associated invariant T cells and disease. Nat Rev Immunol, 2019. doi.org/10.1038/s41577-019-0191-y
5. Flament H et al. Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity. Nat Immunol, 2021. doi.org/10.1038/s41590-021-00870-z.
Ce projet s’inscrit dans la perspective d’une thèse
si oui type de financement prévu : Bourse MESR/LCC
Ecole Doctorale de rattachement : BioSPC
Equipe d’Accueil : : Dendritic cells and B cells in their microenvironment during viral infections and cancer
Intitulé de l’Unité : Université de Paris, INSERM U1016, CNRS UMR8104
Nom du Responsable de l’Unité : Florence Niedergang
Nom du Responsable de l’Équipe : Rémi Cheynier / Anne Hosmalin
Adresse : 27 rue du Faubourg Saint Jacques, 75014 Paris