HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andrews, S. F. Articles by Rawlings, D. J. Search for Related Content PubMed PubMed Citation Articles by Andrews, S. F. Articles by Rawlings, D. J.

Transitional B Cells Exhibit a B Cell Receptor-Specific Nuclear Defect in Gene Transcription¹

Sarah F. Andrews^* and David J. Rawlings^2,*,

^* Department of Immunology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195

The signaling programs that enforce negative selection in early transitional (T1) B cells in response to BCR engagement remain poorly defined. We conducted a comprehensive comparison of BCR signaling in T1 vs follicular mature splenic B cells. T1, in contrast to follicular mature B cells, failed to express key NF-B target genes in response to BCR engagement and exhibited a striking defect in assembly of an active transcriptional complex at the promoter of the survival and proliferative genes A1 and c-Myc. Surprisingly, and contrary to previous models, classical protein kinase C and IB kinase activation, NF-B nuclear translocation and DNA binding were intact in T1 B cells. Furthermore, despite a marked reduction in NFAT1 expression, differential NFAT or AP-1 activation cannot explain this transcriptional defect. Our combined findings demonstrate that T1 B cells are programmed for signal- and stage-specific "nuclear nonresponsiveness" upon encounter with self-Ags.

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 Support for this work has included funds from Cancer Research Institute Training Grant (to S.F.A.) and National Institutes of Health Grants HD37091 and CA81140.

² Address correspondence and reprint requests to Dr. David J. Rawlings, Center for Immunology and Immunotherapies, Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA 98101. E-mail address: drawling{at}u.washington.edu

³ Abbreviations used in this paper: sIgM, surface IgM; pY, phosphotyrosine; InP₃, 1,4,5-triphosphate; PKC/D, protein kinase C/D; Tg, transgenic; KO, knockout; PLC2, phospholipase C2; IKK, IB kinase; 7-AAD, 7-aminoactinomycin D; NP40, Nonidet P-40; fp, forward primer; rp, reverse primer; ChIP, chromatin immunoprecipitation; WT, wild type; FM, follicular mature; PIP, phosphatidyl-inositol 1,4,5-triphosphate; DAG, 1,2-diacylglycerol; cPKC, classical PKC; CsA, cyclosporin A; Pol II, polymerase II.

This article has been cited by other articles:

				W. N. Khan B Cell Receptor and BAFF Receptor Signaling Regulation of B Cell Homeostasis J. Immunol., September 15, 2009; 183(6): 3561 - 3567. [Abstract] [Full Text] [PDF]

				I. Castro, J. A. Wright, B. Damdinsuren, K. L. Hoek, G. Carlesso, N. P. Shinners, R. M. Gerstein, R. T. Woodland, R. Sen, and W. N. Khan B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-{kappa}B2 J. Immunol., June 15, 2009; 182(12): 7729 - 7737. [Abstract] [Full Text] [PDF]