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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 Fest^3,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 917, Institut Fédératif de Recherche 140, Faculté de Médecine, Université Rennes 1, Rennes France; and Laboratoire d’Hématologie et Immunologie, Pôle Cellules & Tissus, and Service d’Hématologie Clinique, Centre Hospitalo-Universitaire Pontchaillou, Rennes, France

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 characterization. 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 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Institut National du Cancer (no. PL070-2005), from the Faculté de Médecine de Rennes, and from the Association pour le Développement de l’Hématologie Oncologie (ADHO). S.L.G. is supported by La Ligue Contre le Cancer/Région Bretagne.

² G.C. and S.L.G. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Thierry Fest, Institut National de la Santé et de la Recherche Médicale, Unité 917, Faculté de Médecine, Université Rennes 1, 2 avenue du Pr Léon Bernard, CS 34317, 35043 Rennes Cedex, France. E-mail address: thierry.fest{at}univ-rennes1.fr

⁴ Abbreviations used in this paper: GC, germinal center; AID, activation-induced cytidine deaminase; B_GC, germinal center B cell; BL, Burkitt’s lymphoma; CSR, class switch recombination; qRT-PCR, quantitative RT-PCR; SHM, somatic hypermutation.

⁵ The online version of this article contains supplemental material.