Hematologic disorder–associated Cxcr4 gain-of-function mutation leads to uncontrolled extrafollicular immune response
Year: 2021
Type: article
Abstract: The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies during infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling caused by defective receptor desensitization leads to exacerbated extrafollicular B-cell response. Using a mouse model bearing a gain-of-function mutation of Cxcr4 described in 2 human hematologic disorders, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and Waldenström macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mechanistic target of rapamycin signaling, cycled more, and differentiated more potently into plasma cells than wild-type B cells after Toll-like receptor (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 after T-independent 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.
Source: Blood
Institutions: Université Paris-Sud, Inserm, Université Paris Cité, Université Paris-Saclay, Inflammation, Microbiome and Immunosurveillance, Ecotaxie, Microenvironnement et développement lymphocytaire, Institut de recherche Saint-Louis, Centre National de la Recherche Scientifique, Hôpital Saint-Louis, Institut Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Fondation Arthritis, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Institut National Du Cancer, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Institut Carnot Santé Animale, National Institutes of Health, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
Awards: G2176860459, G3010527862, Autocrine/paracrine CXCL12/CXCR4-CXCR7 signaling within the bone marrow osteo-vascular niche: impact on lymphoid specification and commitment of hematopoietic stem cells, Analysis of SNARE-mediated regulation of plasma cell biology, Integrative analysis of the biology of plasma cells in health and disease, G6803667113, G7324087099, Université de Paris
OpenAlex ID: W3122855719