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A retraction to this article has been published: Feldhahn et al., J. Exp. Med. 203 (12) 2779
Published 18 November 2002. doi:10.1084/jem.20020881
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© Rockefeller University Press, 0022-1007/2002/11/1291/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 10, November 18, 2002 1291-1305

Silencing of B Cell Receptor Signals in Human Naive B Cells

Niklas Feldhahn1,2, Ines Schwering2, Sanggyu Lee4, Maria Wartenberg3, Florian Klein1,2, Hui Wang1,2, Guolin Zhou4, San Ming Wang4, Janet D. Rowley4, Jürgen Hescheler3, Martin Krönke1, Klaus Rajewsky5, Ralf Küppers2 and Markus Müschen1,2

1 Institute for Medical Microbiology, Immunology and Hygiene
2 Institute for Genetics, University of Cologne, 50931 Köln, Germany
3 Institute for Neurophysiology, University of Cologne, 50931 Köln, Germany
4 Department of Medicine, University of Chicago, Chicago, IL 60637
5 Center for Blood Research, Harvard Medical School, Boston, MA 02115

Address correspondence to Dr. Markus Müschen, Emmy-Noether-Group at the Institute for Genetics, University of Cologne, Room III.10, Weyertal 121, 50931 Köln, Germany. Phone: 49-221-470-3408; Fax: 49-221-470-5170; E-mail: markus.mueschen{at}uni-koeln.de

To identify changes in the regulation of B cell receptor (BCR) signals during the development of human B cells, we generated genome-wide gene expression profiles using the serial analysis of gene expression (SAGE) technique for CD34+ hematopoietic stem cells (HSCs), pre-B cells, naive, germinal center (GC), and memory B cells. Comparing these SAGE profiles, genes encoding positive regulators of BCR signaling were expressed at consistently lower levels in naive B cells than in all other B cell subsets. Conversely, a large group of inhibitory signaling molecules, mostly belonging to the immunoglobulin superfamily (IgSF), were specifically or predominantly expressed in naive B cells. The quantitative differences observed by SAGE were corroborated by semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) and flow cytometry. In a functional assay, we show that down-regulation of inhibitory IgSF receptors and increased responsiveness to BCR stimulation in memory as compared with naive B cells at least partly results from interleukin (IL)-4 receptor signaling. Conversely, activation or impairment of the inhibitory IgSF receptor LIRB1 affected BCR-dependent Ca2+ mobilization only in naive but not memory B cells. Thus, LIRB1 and IL-4 may represent components of two nonoverlapping gene expression programs in naive and memory B cells, respectively: in naive B cells, a large group of inhibitory IgSF receptors can elevate the BCR signaling threshold to prevent these cells from premature activation and clonal expansion before GC-dependent affinity maturation. In memory B cells, facilitated responsiveness upon reencounter of the immunizing antigen may result from amplification of BCR signals at virtually all levels of signal transduction.

Key Words: B cell receptor • IL-4 • ITIM • memory B cells • SAGE


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