La signalisation de CXCR4, un rhéostat de la réponse immunitaire à médiation humorale

CXCR4 est un récepteur de chimiokine qui joue un rôle central dans la migration cellulaire mais également dans d’autres mécanismes essentiels, tels que le développement du système immunitaire. De concert avec son ligand naturel, la chimiokine CXCL12, cet axe de signalisation joue un rôle important dans la biologie des lymphocytes B, des stades précoces de différenciation dans la moelle osseuse à leur activation et différenciation en cellules sécrétrices d’anticorps, aussi appelées plasmocytes. Des mutations gain de fonction de CXCR4 sont retrouvées dans une immunodéficience rare, le Syndrome WHIM. Ces mutations affectent le mécanisme de désensibilisation du récepteur et entraînent un gain de fonction en réponse à CXCL12. Cette revue résume le rôle de CXCR4 dans la réponse immune humorale et, à travers l’étude du Syndrome WHIM, souligne le rôle régulateur essentiel de la désensibilisation de CXCR4 dans ces processus. Des travaux récents rapportent en effet qu’une signalisation correcte de CXCR4 est essentielle pour limiter la réponse immune dite « extra-folliculaire » et pour permettre une protection au long terme assurée par les anticorps

Transinteractome analysis reveals distinct niche requirements for isotype‐based plasma cell subsets in the bone marrow

International audienceBone marrow (BM) long-lived plasma cells (PCs) are essential for long-term protection against infection, and their persistence within this organ relies on interactions with Cxcl12-expressing stromal cells that are still not clearly identified. Here, using single cell RNAseq and in silico transinteractome analyses, we identified Leptin receptor positive (LepR +) mesenchymal cells as the stromal cell subset most likely to interact with PCs within the BM. Moreover, we demonstrated that depending on the isotype they express, PCs may use different sets of integrins and adhesion molecules to interact with these stromal cells. Altogether, our results constitute an unprecedented characterization of PC subset stromal niches and open new avenues for the specific targeting of BM PCs based on their isotype

Hematological disorder associated Cxcr4-gain-of-function mutation leads to uncontrolled extrafollicular immune response Short title: Cxcr4 signaling and the extrafollicular response

International audienceThe extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies upon infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling due to defective receptor desensitization leads to exacerbated extrafollicular B cell response. Using a mouse model bearing a gain of function mutation of Cxcr4 described in two human hematological disorders, WHIM syndrome and Waldenström's Macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mTOR signaling, cycled more and differentiated more potently into plasma cells than wild-type B cells upon TLR stimulation. Moreover, Cxcr4 gain-of-function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies upon Tindependent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response