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The Transcription Factor Fli-1 Modulates Marginal Zone and Follicular B Cell Development in Mice¹

Xian K. Zhang^2,*,, Omar Moussa, Amanda LaRue^,, Sarah Bradshaw^*, Ivan Molano^*, Demetri D. Spyropoulos, Gary S. Gilkeson^*, and Dennis K. Watson

^* Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403; and Department of Pathology and Laboratory of Medicine, Medical University of South Carolina, Charleston, SC 29425

Fli-1 belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1^CTA). Fli-1^CTA/Fli-1^CTA mice had significantly fewer splenic follicular B cells, and an increased number of transitional and marginal zone B cells, compared with wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Ig and other genes implicated in B cell development, including Pax-5, E2A, and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1^CTA/Fli-1^CTA mice. Proliferation of B cells from Fli-1^CTA/Fli-1^CTA mice was diminished, although intracellular Ca²⁺ flux in B cells from Fli-1^CTA/Fli-1^CTA mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recombination were also altered in Fli-1^CTA/Fli-1^CTA mice. Thus, Fli-1 modulates B cell development both centrally and peripherally, resulting in a significant impact on the in vivo immune response.

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 National Institutes of Health Grants PO1-CA78582 (to D.K.W.) and AR051385 and AR054546 (to X.K.Z.), and the Medical Research Service, Department of Veterans Affairs (to G.S.G.).

² Address correspondence and reprint requests to Dr. Xian K. Zhang, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street MSC637, Suite 912, Charleston, SC 29425-6370. E-mail address: zhangjo{at}musc.edu

³ Abbreviations used in this paper: FO, follicular; MZ, marginal zone; CTA, C-terminal transcriptional activation domain; ChIP, chromatin immunoprecipitation; MZP, MZ precursor; KLH, keyhole limpet hemocyanin; BAFF, B cell-activating factor; TNP, 2,4,6-trinitrophenyl.