Products Cited in Publications Worldwide Hematologic disorder-associated Cxcr4 gain-of-function mutation leads to uncontrolled extrafollicular immune response

Hematologic disorder-associated Cxcr4 gain-of-function mutation leads to uncontrolled extrafollicular immune response

Alouche, Nagham; Bonaud, Amelie; Rondeau, Vincent; Hussein-Agha, Rim; Nguyen, Julie; Bisio, Valeria; Khamyath, Melanie; Crickx, Etienne; Setterblad, Niclas; Dulphy, Nicolas; Mahevas, Matthieu; McDermott, David H.; Murphy, Philip M.; Balabanian, Karl; Espeli, Marion

DOI: PMID:

Abstract

The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies during infection. Despite its importance, the mol. 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 hematol. disorders, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and Waldenstrom 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.

Keywords

cxcr4 receptors ; receptor desensitization ; hematological diseases ; mice ; immune response ; b-lymphocytes ; mutation

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