title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
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.
authors.affiliation: Inserm Unité Mixte de Recherche (UMR) S996, Université Paris-Sud, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Clamart, France. karl.balabanian@u-psud.fr
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Emilie
authors.initials: E
authors.lastname: Brotin
authors.forename: Vincent
authors.initials: V
authors.lastname: Biajoux
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouchet-Delbos
authors.forename: Elodie
authors.initials: E
authors.lastname: Lainey
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D001596:Benzylamines; D001853:Bone Marrow / Q000473:pathology; D002451:Cell Compartmentation / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D002908:Chronic Disease; D000080027:Cyclams; D003888:Desensitization, Immunologic; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009503:Neutropenia / Q000097:blood / Q000473:pathology; D019718:Receptors, CXCR4 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor