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NF-kB inhibitor blocks B cell development at two checkpoints

Biao Feng1, Shuhua Cheng1, Warren S Pear2 and Hsiou-Chi Liou1*

Author Affiliations

1 Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA

2 Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA

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Medical Immunology 2004, 3:1  doi:10.1186/1476-9433-3-1

Published: 29 March 2004

Abstract

Members of the NF-kB transcription factor family are differentially expressed in the B cell lineage. Disruption of individual or two NF-kB subunits exhibits distinct defects in B lymphocyte development, activation, and survival. However, the role each NF-kB plays during B cell development has been obscured by molecular compensation. To address this issue, a trans-dominant form of IkBα was transduced into bone marrow cells to act as a pan-inhibitor of NF-kB using a retroviral system. While the development of T-lymphocytes and myeloid cell lineages was not grossly affected by the transduced IkBα gene, a significant reduction in the number and percentage of B lineage cells was apparent in IkBα transduced chimeric mice. IkBα expression decreased the percentage of pre-B and immature B cell subsets in the bone marrow and further impaired the development of follicular mature B cells and marginal zone B cells in the periphery. Introduction of the Bcl-X transgene completely restored the pre-B and immature B cell pool in the bone marrow. However, despite a significant improvement of overall viability of the B cell lineage, Bcl-X expression was insufficient to overcome the maturation block resulting from NF-kB inhibition. Together, our study suggests that NF-kB activity is required for two distinct checkpoints during B cell development: one is for pre-B/immature B cell viability, the other is to provide both survival and maturation signals to ensure the proper development of follicular mature B cells.

Keywords:
NF-kB; IkBα; Bcl-X; B cell development; retroviral gene transduction