Journal
BLOOD
Volume 119, Issue 24, Pages 5722-5730Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-01-403378
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Funding
- Agence Nationale de la Recherche (ANR) [2010 JCJC 1104 01, ANR-07-MRAR-029]
- European Union (INNOCHEM) [LSHB-CT-2005-518167]
- AP-HP
- E-rare [07 E-RARE 013-01]
- ANR (Investissements d'Avenir)
- GIS-Institut des Maladies Rares
- Inserm
- Consortium National de Recherche en Genomique
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Desensitization controls G prote-independent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function. (Blood. 2012; 119(24):5722-5730)
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