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Centroblasts in Vivo the A-Myb Transcription Factor Is a Marker Of The A-Myb Transcription Factor Is a Marker of Centroblasts In Vivo Josée Golay, Vania Broccoli, Giuseppe Lamorte, Carlo Bifulco, Carlo Parravicini, Arnold Pizzey, N. Shaun B. Thomas, Domenico This information is current as Delia, Paola Ferrauti, Domenico Vitolo and Martino Introna of October 4, 2021. J Immunol 1998; 160:2786-2793; ; http://www.jimmunol.org/content/160/6/2786 Downloaded from References This article cites 47 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/160/6/2786.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 4, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The A-Myb Transcription Factor Is a Marker of Centroblasts In Vivo1 Jose´e Golay,2* Vania Broccoli,* Giuseppe Lamorte,† Carlo Bifulco,‡ Carlo Parravicini,‡ Arnold Pizzey,§ N. Shaun B. Thomas,§ Domenico Delia,¶ Paola Ferrauti,i Domenico Vitolo,i and Martino Introna* The A-Myb transcription factor is structurally related to the c-myb proto-oncogene and is involved in the control of proliferation and/or differentiation of mature B lymphocytes. We have shown previously by PCR analysis that A-myb is preferentially expressed in CD381CD392sIgM2 mature B cells. We demonstrate here, using in situ hybridization, that A-myb expression is restricted to the dark zone of human tonsils and lymph nodes. Furthermore, we show that A-Myb expression is cell cycle regulated both in tonsillar B cells and in Burkitt’s lymphoma cell lines, being detectable only in the S and G2/M phases of the cell cycle and not in m Downloaded from G0/G1 phase. Strong proliferation of resting human B cells induced in vitro by a variety of physiologic signals, including anti- , CD40 ligand, IL-2, IL-4, IL-6, IL-13, IFN-g, TNF-a, anti-CD19, and anti-CD20, failed to induce A-myb expression, suggesting that proliferation alone is not sufficient for A-myb expression in the absence of induction of a true centroblast phenotype. Finally, we show that differentiation of germinal center B cells in vitro toward either memory or plasma cells is accompanied by rapid down-regulation of A-myb expression. We conclude that A-myb is a marker of centroblasts generated in vivo. The Journal of Immunology, 1998, 160: 2786–2793. http://www.jimmunol.org/ -Myb belongs to the myb family of transcription factors, of mature tonsillar B lymphocytes, with the phenotype CD381, which include in mammals the v-myb oncogene, its nor- CD392, and mostly sIgM2 and is therefore presumably localized A mal cellular equivalent c-myb, and the two structurally within GC (19, 20). Furthermore, the study of a panel of B cell related B-myb and A-myb genes (1–4). All members of the Myb lines and fresh B leukemia samples representing B cell differen- family have been shown to be involved in the control of prolifer- tiation from pre-B cells to plasma cells showed that A-Myb is ation and/or differentiation of different hemopoietic cells (3, 4). In expressed only in Burkitt’s lymphoma cells, presumably represent- particular, v-Myb and c-Myb block the differentiation of myeloid, ing the neoplastic counterpart of GC cells, and in a fraction of erythroid, and immature multipotent progenitors (5–8). C-Myb is B-CLL (21). These findings have led to the hypothesis that A-Myb by guest on October 4, 2021 required for the proliferation of hemopoietic cell lines of different plays a role in the control of proliferation and/or differentiation of lineages (9), and c-myb knockout animals die in utero due to a mature B cells (22). Very recently, this hypothesis has gained complete block of fetal hemopoiesis (10). B-Myb has been shown much strength from transgenic experiments. Mice expressing ec- to be required for the proliferation of many cell types including topic A-Myb in a wide range of tissues showed specific deregu- fibroblasts and smooth muscle cells, and its expression, in general, lation of the B cell compartment, with hyperplasia of the spleen correlates strictly with proliferation (11–14). The third member of and lymph nodes and accumulation of a mature polyclonal B cell the family, A-Myb, shows the most restricted pattern of expres- 1 sion: in the adult mouse, it is expressed in some proliferating neu- population with a CD38 phenotype (23). ronal precursor cells, in spermatocytes, breast ductal epithelium, Germinal centers are central to the differentiation and function and germinal center (GC)3 B lymphocytes (15–18). In human he- of B lymphocytes (24–26). Naive mature B lymphocytes migrate mopoietic cells, A-Myb has been detected only in a subpopulation from the bone marrow to peripheral lymphoid organs. Upon Ag encounter in the T cell areas of spleen and lymph nodes, B cells migrate to the follicles where the activated cells will form GC. GC † *Istituto Ricerche Farmacologiche “Mario Negri,” Fondazione Matarelli, Hospital B cells undergo extremely rapid proliferation (estimated doubling Fatebenefratelli e Oftalmico, and ‡Department of Pathological Anatomy, Hospital L. Sacco, Milan, Italy; §Department of Hematology, University College London Medical time, 6–7 h) and somatic mutation of their Ig gene within the dark School, London, United Kingdom; and ¶Department of Experimental Oncology A, zone of GC, which contains mostly large proliferating B cells or Istituto Nazionale dei Tumori, Milan, and iDepartment of Experimental Medicine and Pathology, Immunopathology Section, Universita`di Roma La Sapienza, Rome, Italy centroblasts. Further differentiation of centroblasts to centrocytes Received for publication July 28, 1997. Accepted for publication November 18, 1997. is accompanied by migration to the light zone of GC and arrest of The costs of publication of this article were defrayed in part by the payment of page the proliferation. The light zone contains the follicular dendritic charges. This article must therefore be hereby marked advertisement in accordance cells (FDC) and GC helper T cells, which are thought to be im- with 18 U.S.C. Section 1734 solely to indicate this fact. portant in regulating the B cell differentiation processes taking 1 This work was supported in part by the Italian Association for Cancer Research place in this region of GC: apoptosis of B cells with low affinity for (AIRC) and the Istituto Superiore di Sanita`(Rome, Italy, AIDS project). J.G. is a 1997 Fellow of the Angelo and Angela Valenti Foundation, Milan, Italy. N.S.B.T. is sup- the Ag, leading to affinity maturation, and differentiation to mem- ported by the Kay Kendall Leukaemia Fund. G.L. is supported by the Associazione ory cells or to preplasma cells, which will then migrate to the bone Italiana Leucemia (AIL), Milan, Italy. marrow for full differentiation to plasma cells. The latter processes 2 Address correspondence and reprint requests to Dr. Jose´e Golay, Istituto Ricerche Farmacologiche “Mario Negri,” via Eritrea 62, 20157 Milano, Italy. E-mail address: also involve isotype switching for the production of different Ig [email protected] classes. Thus, the very fine compartmentalization of the GC has 3 Abbreviations used in this paper: GC, germinal center; CD40L, CD40 ligand. allowed a precise understanding of the sequence of events that Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 2787 takes place in GC, through the study of cell markers and morphol- remove unhybridized and nonspecifically bound probe. Autoradiography ogy, expression of specific genes, and the mutation and recombi- was performed with Kodak NT/B2 emulsion. Exposure times were be- nation of Ig genes in normal and genetically modified animals tween 2 and 3 wk. After developing, the sections were mounted in DPX (Merck, Darmstadt, Germany). Adjacent sections were processed for his- (24–26). In turn, knowledge of the localization of new gene prod- tologic staining or immunohistochemistry. ucts within GC can indicate the potential function of such prod- ucts. Previous experiments using purified tonsillar B cell subpopu- Proliferation and differentiation assays in vitro lations had suggested that the A-Myb transcription factor is Recombinant trimeric human CD40 ligand (CD40L) was obtained from expressed by GC B cells, but its possible subcompartmentalization Immunex (Seattle, WA) and used at 1 mg/ml. rIL-2 (Eurocetus, Amster- within this structure had not been investigated (20). Given the dam, Holland) was used at 200 U/ml, rIL-4 (Immunex, Seattle, WA) at 50 important role demonstrated for this transcription factor in B cell ng/ml, rIL-6 (Serono, Roma, Italy) at 5 ng/ml, rIL-10 (Shering-Plough, Milano, Italy) at 20 ng/ml, and rIL-13 (Sanofi, Montpellier, France) at 40 differentiation, our goal was to determine the pattern of A-Myb ng/ml; IFN-g was from Roussel-UCLAF (Paris, France) at 200 U/ml and expression in GC in vivo and in models of B cell proliferation and TNF-a (BASF Pharma Knoll, Ludwigshafen, Germany) at 10 ng/ml. 9 m differentiation in vitro. We show that A-Myb is specifically ex- F(ab )2 Goat anti-human -chain (Cappel, Organon Teknika Corp., West m pressed in proliferating centroblasts generated in vivo and is not Chester, PA) was used at 25 g/ml.
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