Impact of Cxcr4 signaling on plasma cell metabolism and fitness in health and disease.
Responsable du Stage :Dr Marion Espéli
Tél : …0142499551… E-mail: firstname.lastname@example.org
Institut de Recherche Saint Louis
Résumé du Projet de Stage
One axis of our laboratory focuses on plasma cells (PCs) that correspond to the last stage of B cell differentiation and are the cells responsible for antibody production and secretion. PCs are essential for potent and long-lasting immunity but can also have pathologic roles in autoimmunity and inflammatory diseases and can give rise to plasmacytomas. PCs are generated in secondary lymphoid organs following antigenic challenges and will survive for a couple of days unless they migrate to dedicated niches within the bone marrow (BM) in which they can persist for several months/years ensuring long-term protection against reinfection. We recently showed that a fine regulation of the signaling axis induced by the chemokine receptor Cxcr4 was essential for PC generation but also for their migration in the BM and their long term persistence (Biajoux et al. Cell Reports 2016, Alouche et al. Blood 2021). Interestingly, gain of function mutations of CXCR4 were reported in two pathologies; the WHIM syndrome, a rare immunodeficiency and Waldenström’s macroglobulinemia, a lymphoplasmacytoma. We previously published a mouse model for the WHIM syndrome (Cxcr4+/1013 mouse model; Balabanian et al. Blood 2012) and recently developed a mouse model for Waldenström’s macroglobulinemia by crossing the Cxcr4+/1013 mouse model with a mouse model bearing a gain of function mutation of MyD88 observed in 90% of Waldenström’s macroglobulinemia patients (Ouk et al. Frontiers in Immunology 2021). Using these two mouse models and RNAseq analyses, we recently showed that alteration of the Cxcr4 signalling was associated with disturbed metabolism of PCs.
Based on these results, the goal of this MA project is thus two-fold:
- Validate at the fonctional level the RNAseq results and in particular the implication of Cxcr4 signaling in mitochondrial metabolism in PCs. This will be done by flow cytometry, immunofluorescence and Seahorse assay. All these techniques are routinely used in the laboratory ensuring the feasibility of this part of the project.
- Correct the identified deregulations with specific pharamcological modulators to assess their impact on PC generation and survival in vitro. This approach has already been used in the laboratory (Alouche et al. Blood 2021, Bonaud et al. Biorxiv 2022) and all the tools are in place.
Altogether, this project will establish whether Cxcr4 signaling regulates the generation, the fitness and the fate of PCs via metabolic reprograming and will shed light on the consequences of disruption of this signaling in pathologies presenting gain of function mutations of Cxcr4.
Bonaud A, Gargowitsch L, Gilbert SM, Rajan E, Canales-Herrerias P, Stockholm D, Rahman NF, Collins MO, Hill DL, Alloatti A, Alouche N, Balor S, Soldan V, Gillet D, Barbier J, Bachelerie F, Smith KGC, Bruhns P, Amigorena S, Balabanian K, Linterman MA, Peden AA, Espéli M. 2022. Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics. BioRxiv 2022.01.14.476154
Ouk C, Roland L, Gachard N, Poulain S, Oblet C, Rizzo D, Saintamand A, Lemasson Q, Carrion C, Thomas M, Balabanian K, Espéli M, Parrens M, Soubeyran I, Boulin M, Faumont N, Feuillard J, Vincent-Fabert C. 2021.Continuous MYD88 Activation Is Associated With Expansion and Then Transformation of IgM Differentiating Plasma Cells. Front Immunol. 2021 May 4;12:641692. PMID : 34017329, IF: 7.56
Alouche N#, Bonaud A#, Rondeau V, Hussein-Agha R, Nguyen J, Bisio V, Khamyath M, Crickx E, Setterblad N, Dulphy N, Mahevas M, McDermott DH, Murphy P, Balabanian K*, Espéli M*. 2021 Hematological disorder associated Cxcr4-gain-of-function mutation leads to uncontrolled extrafollicular immune response. Blood. 2021 Jan 21:blood.2020007450. #co-first, *co-last. PMID : 33512437, IF =23.6
Biajoux V#, Natt J#, Freitas C, Alouche N, Sacquin A, Hemon P, Gaudin F, Fazilleau N, Espéli M*, Balabanian K*. 2016. Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization. Cell Rep. 2016 Sep 27;17(1):193-205. #co-first, *co-last. PMID : 27681431, IF =9.42
Ce projet s’inscrit-il dans la perspective d’une thèse :
si oui type de financement prévu : Financement par l’ED ou ANR
Ecole Doctorale de rattachement : ED 561 : « Hématologie, Oncogénèse et Biothérapies »
Intitulé de l’Unité : Inserm U1160 « Ecotaxie, Microenvironnement et Developpement lymphocytaire »
Equipe d’Accueil : Chimiokines, niches lymphoïdes et immunopathologie (Equipe 1)
Nom du Responsable de l’Unité : Pr. Antoine Toubert
Nom du Responsable de l’Équipe :Drs. Karl Balabanian et Marion Espéli
Adresse : Inserm U1160, Institut de Recherche Saint Louis, 1 avenue Claude Vellefaux 75010 PARIS