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B Cells Centrocytes Within Human Germinal Center Discriminates CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells This information is current as of September 28, 2021. Gersende Caron, Simon Le Gallou, Thierry Lamy, Karin Tarte and Thierry Fest J Immunol 2009; 182:7595-7602; ; doi: 10.4049/jimmunol.0804272 http://www.jimmunol.org/content/182/12/7595 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2009/06/02/182.12.7595.DC1 Material http://www.jimmunol.org/ References This article cites 27 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/182/12/7595.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells1 Gersende Caron,2*† Simon Le Gallou,2* Thierry Lamy,*‡ Karin Tarte,*† and Thierry Fest3*† The human germinal center is a highly dynamic structure where B cells conduct their terminal differentiation and traffic following chemokine gradients. The rapidly dividing centroblasts and the nondividing centrocytes represent the two major B cell subsets present in germinal center and also the most common normal counterparts for a majority of lymphomas. CD77 expression was previously associated to proliferating centroblasts undergoing somatic hypermutation, but data from transcriptional studies demonstrate that CD77 is not a reliable marker to discriminate human centroblasts from centrocytes. Herein we were able for the first time to separate these two subpopulations based on the expression of the chemokine receptor CXCR4 allowing their char- acterization. Phenotypic and functional features were especially explored, giving an accurate definition of CXCR4؉ centroblasts ؊ ؉ ؊ compared with CXCR4 centrocytes. We show that CXCR4 and CXCR4 germinal center B cells present a clear dichotomy in Downloaded from terms of proliferation, transcription factor expression, Ig production, and somatic hypermutation regulation. Microarray analysis identified an extensive gene list segregating these B cells, including highly relevant genes according to previous knowledge. By gene set enrichment analysis we demonstrated that the centroblastic gene expression signature was significantly enriched in Burkitt’s lymphomas. Collectively, our findings show that CXCR4 expression can properly separate human centroblasts from centrocytes and offer now the possibility to have purified normal counterparts of mature B cell-derived malignancies. The Journal of Im- munology, 2009, 182: 7595–7602. http://www.jimmunol.org/ fter Ag encounter in the edge of the T cell zone, Ag- diffuse large B cell lymphoma, and Burkitt’s lymphoma (BL) specific B cells, in the company of Ag-primed T cells, (2). Thus, a better knowledge of centroblast and centrocyte bi- will migrate into the B follicle of peripheral lymphoid ology, through the comprehensive molecular and functional A 4 tissues to generate a germinal center (GC) reaction, the functional study of highly pure cell populations, is a prerequisite to fully niche required for the production of high-affinity Abs during adap- understand lymphomagenesis. No relevant surface marker is tive immune response. Around days 7–10 after initial Ag priming, available to functionally separate human centroblasts from cen- the GC follicle is polarized into a so-called “dark zone” of rapidly trocytes. So far, only CD77 expression was used to characterize dividing centroblasts processing Ab maturation and a “light zone” proliferating centroblasts engaged in the somatic hypermutation by guest on September 28, 2021 of small nondividing centrocytes that undergo selection based on (SHM) process, whereas CD77 is no longer expressed on cen- the affinity of their surface Igs for the inducing Ag. Finally, cells trocytes involved in the class switch recombination (CSR) pro- proceed to the terminal differentiation into Ab-producing plasma cess (3, 4). However, recent gene expression studies show that cells or memory B cells (1). only limited differentially expressed genes were detected when GC B cells (BGC) are thought to be the normal counterpart of BGC were segregated according to the CD77 marker (5–7). Re- some human B cell malignancies, including follicular lymphoma, markably, CD77Ϫ cells represent a heterogeneous subset, which share the CD77ϩ cell proliferation program, DNA damage, and *Institut National de la Sante´et de la Recherche Me´dicale, Unite´917, Institut Fe´d- replication checkpoint activation and polycomb group protein e´ratif de Recherche 140, Faculte´deMe´decine, Universite´Rennes 1, Rennes France; expression (8), suggesting that centroblasts comprise cells lack- and †Laboratoire d’He´matologie et Immunologie, Poˆle Cellules & Tissus, and ‡Ser- ing CD77. These data reinforced the need to have a better vice d’He´matologie Clinique, Centre Hospitalo-Universitaire Pontchaillou, Rennes, France marker to discriminate human BGC subsets. Received for publication December 22, 2008. Accepted for publication April 13, In mice, CXCR4 expression on BGC clusters the proliferating 2009. centroblasts in a unique site of the GC, thereby creating the dark The costs of publication of this article were defrayed in part by the payment of page zone rich in CXCL12, whereas the CXCR5-CXCL13 pair at- charges. This article must therefore be hereby marked advertisement in accordance tracts BGC to the light zone (9). This compartmentalization is with 18 U.S.C. Section 1734 solely to indicate this fact. highly dynamic, and data recently confirmed by two-photon in- 1 This work was supported by grants from the Institut National du Cancer (no. PL070- travital microscopic studies described a B cell trafficking within 2005), from the Faculte´deMe´decine de Rennes, and from the Association pour le De´veloppement de l’He´matologie Oncologie (ADHO). S.L.G. is supported by La each zone and interzonal migration of infrequent cells that may Ligue Contre le Cancer/Re´gion Bretagne. repeat one or several rounds of Ag-driven mutations (10–13). 2 G.C. and S.L.G. contributed equally to this study. Moreover, a mathematical modeling of BGC migration suggests 3 Address correspondence and reprint requests to Dr. Thierry Fest, Institut National de that the spatiotemporal GC organization is associated to a tran- la Sante´et de la Recherche Me´dicale, Unite´917, Faculte´deMe´decine, Universite´ sient sensitivity of centroblasts and centrocytes to CXCL12 and Rennes 1, 2 avenue du Pr Le´on Bernard, CS 34317, 35043 Rennes Cedex, France. E-mail address: [email protected] to CXCL13, respectively (14). Thus, chemokine receptor ex- 4 Abbreviations used in this paper: GC, germinal center; AID, activation-induced pression levels by B cells and their regulation appear to be cytidine deaminase; BGC, germinal center B cell; BL, Burkitt’s lymphoma; CSR, critical for GC organization. To gain insight into the human class switch recombination; qRT-PCR, quantitative RT-PCR; SHM, somatic B compartmentalization, we analyzed the expression of both hypermutation. GC CXCR4 and CXCR5 on BGC. We observed that CXCR4 mem- Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 brane expression segregated nicely the cells into a positive and www.jimmunol.org/cgi/doi/10.4049/jimmunol.0804272 7596 CXCR4 AND HUMAN GC B CELL SUBSETS ⌬⌬ Table I. List of Abs used for flow cytometry analysis and cell sorting pressed relative to total B cell fractions using the CT comparative method. Anti-Human Abs Clone Isotype Source Gene expression profile analysis IgD-FITC IA6-2 IgG2a BD Biosciences Total RNA from each purified population was extracted using an RNeasy IgG-FITC G18-145 IgG1 BD Biosciences CD77-FITC 5B5 IgM BD Biosciences kit (Qiagen), and RNA integrity was assessed using a bioanalyzer (Agilent CXCR4-PE 12G5 IgG2a BD Biosciences Technologies). The hybridization was done onto Human Genome U133 CXCR5-PE 51505 IgG2b R&D Systems Plus 2.0 GeneChips (Affymetrix) (data are available at www.ncbi. CD10-energy-coupled ALB1 IgG1 Beckman Coulter nlm.nih.gov/geo/query/acc.cgi?acc, accession no. GSE15271) following a dye standardized protocol develop by the Core Facility Platform of the Centre CD27-PE Cy5 1A4-CD27 IgG1 Beckman Coulter Hospitalier Universitaire de Montpellier. A total of four human tonsils have CD38-PE Cy5 LS198-4-3 IgG1 Beckman Coulter ϩ Ϫ been sorted for CXCR4 and CXCR4 BGC. The normalized hybridization CD44-PE Cy7 IM7 IgG2b (rat) eBioscience intensity for each probe set was calculated using the GeneChip robust CD19-Pacific Blue HIB19 IgG1 eBioscience multiarray analysis method; background noise was decreased by elim- inating probe set with a CV Ͻ0.8. Both analyses
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