ABSTRACT
The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.
Subject(s)
Cell Differentiation/genetics , Hematopoietic Stem Cells/metabolism , Lymphocytes/metabolism , Receptors, CXCR4/genetics , Adult , Animals , Bone Marrow Cells/metabolism , Bone Marrow Transplantation/methods , Cell Survival/genetics , Child , Flow Cytometry , Gene Expression , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Lymphocyte Count , Mice, Transgenic , Mutation , Primary Immunodeficiency Diseases , Receptors, CXCR4/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Spleen/cytology , Spleen/metabolism , Warts/genetics , Warts/metabolismABSTRACT
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.
Subject(s)
B-Lymphocyte Subsets/immunology , Bone Marrow/immunology , Desensitization, Immunologic , Immunologic Deficiency Syndromes/immunology , Plasma Cells/immunology , Receptors, CXCR4/immunology , Warts/immunology , Animals , Antibodies/blood , B-Lymphocyte Subsets/drug effects , B-Lymphocyte Subsets/pathology , Bone Marrow/drug effects , Bone Marrow/pathology , Cell Differentiation , Cell Movement , Disease Models, Animal , Gene Expression , Gene Knock-In Techniques , Germinal Center , Haptens , Hemocyanins/administration & dosage , Humans , Immunity, Humoral , Immunization , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/pathology , Mice , Mice, Transgenic , Ovalbumin/administration & dosage , Plasma Cells/drug effects , Plasma Cells/pathology , Primary Immunodeficiency Diseases , Receptors, CXCR4/genetics , Signal Transduction , Warts/genetics , Warts/pathologyABSTRACT
Recent studies have highlighted the importance of understanding the molecular determinants of CXCL12-mediated effects in cancers. Once previously thought to interact exclusively with CXCR4, CXCL12 also binds with high affinity to CXCR7 (recently renamed ACKR3), which belongs to an atypical chemokine receptor family whose members fail to activate Gαi proteins but interact with ß-arrestins. In addition to its capacity to control CXCL12 bioavailability, ACKR3 can either enhance or dampen CXCR4-mediated signaling and activity. In light of the most recent findings, we have examined the role of ACKR3 in cancer, including a subset of virus-related cancers.
Subject(s)
Chemokine CXCL12/metabolism , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Receptors, CXCR/metabolism , Signal Transduction , Tumor Virus Infections/metabolism , Animals , Arrestin/metabolism , GTP-Binding Protein alpha Subunits , Humans , Neoplasms/pathology , Neoplasms/virology , Receptors, CXCR4/metabolism , Tumor Virus Infections/pathologyABSTRACT
BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by B-cell hyper-reactivity and the production of pathogenic anti-nuclear-directed auto-antibodies (Abs). B-cell ontogeny is partly dependent on the CXCL12/CXCR4 axis for which the contribution to SLE pathogenesis remains unclear. CXCR7, the novel receptor for CXCL12, is differentially expressed among memory B-cell subsets. However, its biological role in SLE remains to be explored. METHODS: Relative CXCR4 and CXCR7 expression levels were compared by quantitative PCR in leukocytes from blood samples of 41 Mexican Mestizos patients with SLE and 45 ethnicity-matched healthy subjects. Intracellular and membrane expression of both receptors was analyzed by flow cytometry in naive and Ab-secreting B cells. B-cell responsiveness to CXCL12 was investigated using Transwell-based chemotaxis assays. Data were analyzed using the Kruskal-Wallis test for comparisons of values amongst healthy controls and patients with inactive or active SLE, and non-parametrically using the Mann-Whitney U-test for multiple comparisons and unpaired samples. Correlations were determined by Spearman's ranking. RESULT: SLE leukocytes displayed reduced levels of CXCR4 and CXCR7 transcripts. In SLE patients, a significant defect in CXCR4 expression was detected at the surface of naive and Ab-secreting B cells, associated with an abnormal intracellular localization of the receptor. CXCR7 predominantly localized in cytosolic compartments of B cells from healthy and SLE individuals. Disease activity did not impact on these expression patterns. Altered receptor compartmentalization correlated with an impaired CXCL12-promoted migration of SLE B cells. CONCLUSIONS: Our data highlight a down-regulation of CXCL12 receptors on circulating B cells from SLE patients that likely influences their migratory behavior and distribution.
