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International Immunology, Vol. 14, No. 8, pp. 905-916, August 2002
© 2002 Japanese Society for Immunology

c-Rel regulation of the cell cycle in primary mouse B lymphocytes

Constance Y. Hsia1, Shuhua Cheng2, Alexander M. Owyang1, Steven F. Dowdy3 and Hsiou-Chi Liou2

1 Immunology Program and 2 Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, 515 East 71st Street, New York, NY 10021, USA 3 Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093, USA

Correspondence to: H.-C. Liou; E-mail: hcliou{at}med.cornell.edu
Transmitting editor: L. H. Glimcher

Surface-expressed BCR mediates the proliferation and expansion of antigen-specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c-Rel, a proto-oncogenic member of the NF-{kappa}B transcription factor family, is essential to BCR-mediated proliferation and cell cycle progression. Splenic B cells obtained from gene-targeted c-Rel knockout mice display a defective proliferation response to antigen receptor cross-linking, resulting in G1 arrest. At the molecular level, we see that BCR stimulation of resting c-Rel–/– B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G1 phase cyclin-dependent kinase (CDK) activity. c-Rel-deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G1 to S phase transition. Down-regulation of the pRb-related p130 protein during the G0 to G1 transition and removal of the CDK inhibitor p27KIP1 in late G1 parallel that of wild-type cells, suggesting that Rel-deficient B cells can exit the G0 resting state and enter G1 phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response.

Keywords: antigen receptor, B cell, c-Rel knockout, cyclin, NF-{kappa}B


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