Hematological disorder associated Cxcr4-gain-of-function mutation leads to uncontrolled extrafollicular immune response Short title: Cxcr4 signaling and the extrafollicular response - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Blood Année : 2021

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

Etienne Crickx

Résumé

The 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.
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Dates et versions

hal-03314577 , version 1 (05-08-2021)

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Nagham Alouche, Amélie Bonaud, Vincent Rondeau, Rim Hussein-Agha, Julie Nguyen, et al.. Hematological disorder associated Cxcr4-gain-of-function mutation leads to uncontrolled extrafollicular immune response Short title: Cxcr4 signaling and the extrafollicular response. Blood, 2021, 137 (22), pp.3050-3063. ⟨10.1182/blood.2020007450⟩. ⟨hal-03314577⟩
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