Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

K Balabanian, E Brotin, V Biajoux… - Blood, The Journal …, 2012 - ashpublications.org
K Balabanian, E Brotin, V Biajoux, L Bouchet-Delbos, E Lainey, O Fenneteau, D Bonnet
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
Desensitization controls G protein–dependent 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 …
Abstract
Desensitization controls G protein–dependent 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.
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