Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization
CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lym...
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Veröffentlicht in: | Cell reports (Cambridge) 2016-09, Vol.17 (1), p.193-205 |
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Sprache: | eng |
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Zusammenfassung: | CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lymphopenia, patients mount an immune response but fail to maintain it over time. Using a knockin mouse model phenocopying WS, we showed that, counter-intuitively, a gain of Cxcr4 function inhibited the maintenance of antibody titers after immunization. Although the Cxcr4 mutation intrinsically and locally promoted germinal center response and PC differentiation, antigen-specific PCs were barely detected in the BM, a defect mirrored by early accumulation of immature plasmablasts potentially occupying the survival niches for long-lived PCs. Therefore, fine-tuning of Cxcr4 desensitization is critically required for efficient PC differentiation and maintenance, and absence of such a regulatory process may account for the defective humoral immunity observed in WS patients.
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•Cxcr4 desensitization controls plasma cell differentiation•Cxcr4 desensitization inhibits plasmablast accumulation in the bone marrow•Cxcr4 desensitization is required for antigen-specific plasma cell trafficking•Cxcr4 desensitization is required for maintaining antigen-specific antibody titers
Using a mouse model harboring a gain-of-function mutation in Cxcr4, Biajoux et al. show that Cxcr4 desensitization is a crucial regulatory mechanism controlling plasma cell differentiation and trafficking. This mutation is associated with an accumulation of plasmablasts in the bone marrow and defective maintenance of serum antibody titers. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2016.08.068 |