Abstract

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 therare 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.

Highlights

  • The warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WS) is a rare combined immuno-hematologic disorder characterized by chronic pan-leukopenia, including circulating B and T lymphocytes (Dotta et al, 2011; Kawai and Malech, 2009)

  • A Gain of Cxcr4 Function in B and T Cells Is Sufficient to Induce a Peripheral Lymphopenia In-depth analysis of the blood compartment in non-manipulated WT and Cxcr4+/1013 mice revealed that mutant mice harbored a severe lymphopenia predominantly affecting naive CD4+ T cells and mature recirculating B cells (Figure 1A)

  • Cxcr4 is expressed widely, and so we sought to determine whether this circulating lymphopenia and abnormal lymphocyte compartmentalization in secondary lymphoid organs (LOs) from Cxcr4+/1013 mice was due to a lymphocyte-intrinsic defect or an alteration of the LO microenvironment

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Summary

Introduction

The warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WS) is a rare combined immuno-hematologic disorder characterized by chronic pan-leukopenia, including circulating B and T lymphocytes (Dotta et al, 2011; Kawai and Malech, 2009). Cellular and humoral immune responses are largely intact after immunization, but oligoclonality, impaired memory B cell function, and vaccination failures have been reported (Gulino et al, 2004; Handisurya et al, 2010; Mc Guire et al, 2010). Together these suggest preserved short-term adaptive immune responses but a defect in the durability of protective memory humoral responses. Serum immunoglobulin M (IgM) and IgG levels were increased in non-manipulated mutant mice compared to their wild-type (WT) littermates, suggesting alterations in the quality and control of the humoral immune response in this model

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