Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization.
CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lymphopenia, patients mount an immune response but fail to maintain it over time. Using a knockin mouse model phenocopying WS, we showed that, counter-intuitively, a gain of Cxcr4 function inhibited the maintenance of antibody titers after immunization. Although the Cxcr4 mutation intrinsically and locally promoted germinal center response and PC differentiation, antigen-specific PCs were barely detected in the BM, a defect mirrored by early accumulation of immature plasmablasts potentially occupying the survival niches for long-lived PCs. Therefore, fine-tuning of Cxcr4 desensitization is critically required for efficient PC differentiation and maintenance, and absence of such a regulatory process may account for the defective humoral immunity observed in WS patients.
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France.
Vincent
V
Biajoux
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France.
Jessica
J
Natt
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France.
Christelle
C
Freitas
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France.
Nagham
N
Alouche
INSERM U1043, Toulouse 31300, France; CNRS U5282, Toulouse 31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse 31300, France.
Antoine
A
Sacquin
Plateforme d'Histologie (PHIC), Institut Paris-Saclay d'Innovation Thérapeutique (IPSIT), Clamart 92140, France.
Patrice
P
Hemon
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France.
Françoise
F
Gaudin
INSERM U1043, Toulouse 31300, France; CNRS U5282, Toulouse 31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse 31300, France.
Nicolas
N
Fazilleau
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France. Electronic address: marion.espeli@u-psud.fr.
Marion
M
Espéli
INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Université Paris-Sud and Université Paris-Saclay, Clamart 92140, France. Electronic address: karl.balabanian@u-psud.fr.
Karl
K
Balabanian
D000818:Animals; D000906:Antibodies / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D018858:Germinal Center; D006241:Haptens; D006433:Hemocyanins / Q000008:administration & dosage; D006801:Humans; D056724:Immunity, Humoral; D007114:Immunization; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014860:Warts / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; D000906:Antibodies; C514936:CXCR4 protein, mouse; D006241:Haptens; D019718:Receptors, CXCR4; D010047:Ovalbumin; D006433:Hemocyanins