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B21
* Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136;
Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224; and
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01665
Signaling from the BCR and B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21int-T2) B cells during selection processes to generate mature B lymphocytes. However, molecular mechanisms underlying the differential sensitivity of transitional B cells to apoptosis remain unclear. In this study, we demonstrate that BCR signaling induced more long-term c-Rel activation in T2 and mature than in T1 B cells leading to increased expression of anti-apoptotic genes as well as prosurvival BAFF-R and its downstream substrate p100 (NF-
B2). Sustained c-Rel activation required de novo c-Rel gene transcription and translation via Btk-dependent mechanisms. Like T1 cells, mature B cells from Btk- and c-Rel-deficient mice also failed to activate these genes. These findings suggest that the gain of survival potential within transitional B cells is dependent on the ability to produce a long-term c-Rel response, which plays a critical role in T2 B cell survival and differentiation in vivo by inducing anti-apoptotic genes, BAFF-R and NF-B2, an essential component for BAFF-R survival signaling. Thus, acquisition of resistance to apoptosis during transitional B cell maturation is achieved by integration of BCR and BAFF-R signals.
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 study is supported in part by National Institutes of Health AI060729 (to W.N.K.), AI041054 and AI057463 (to R.T.W), AI043534 (to R.M.G), P30DK32520 (to University of Massachusetts Medical Flow Cytometry Core) and DK32520 (to the University of Miami Miller School of Medicine Diabetes and Endocrinology Center). K.L.H and N.P.S. are supported by NIH T32 HL69715–0, I.C. by NIH T32 CA09385–20 and J.A.W. by NIH 5 T32 HL069765. B.D. and R.S. are supported by intramural research program of the National Institute of Health on Aging, Baltimore, MD.
2 I.C. and J.A.W. contributed equally to this study.
3 Current address: MedImmune, One MedImmune Way, Department of Inflammation and Autoimmunity, Gaithersburg, MD, 20878.
4 Current address: Brigham and Women’s Hospital, Harvard Medical School, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115.
5 Address correspondence and reprint requests to Dr. Wasif N. Khan, Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, 1600 Northwest 10th Avenue, Miami, FL 33136. E-mail address: wnkhan{at}med.miami.edu
6 Abbreviations used in this paper: Fo B, follicular B cell; MZ, marginal zone; BAFF, B cell activating factor; Btk, Bruton’s tyrosine kinase; WT, wild type; FCM, flow cytometric; Tg, transgenic; qRT-PCR, quantitative RT-PCR.
This article has been cited by other articles:
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  K. L. Hoek, G. Carlesso, E. S. Clark, and W. N. Khan Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling J. Immunol., November 1, 2009; 183(9): 5630 - 5643. [Abstract] [Full Text] [PDF]
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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]
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