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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4088-4096.
Prepublished online as a Blood First Edition Paper on August 26, 2004; DOI 10.1182/blood-2003-12-4291.
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IMMUNOBIOLOGY
Tracking CD40 signaling during germinal center development
Katia Basso,
Ulf Klein,
Huifeng Niu,
Gustavo A. Stolovitzky,
Yuhai Tu,
Andrea Califano,
Giorgio Cattoretti, and
Riccardo Dalla-Favera
From the Institute for Cancer Genetics, the Department of Pathology and Genetics and Development, and the Joint Centers for Systems Biology, Columbia University, New York, NY; and IBM T. J. Watson Research Center, Yorktown Heights, NY.
Substantial evidence indicates that signaling through the CD40 receptor (CD40) is required for germinal center (GC) and memory B-cell formation. However, it is not fully understood at which stages of B-cell development the CD40 pathway is activated in vivo. To address this question, we induced CD40 signaling in human transformed GC B cells in vitro and identified a CD40 gene expression signature by DNA microarray analysis. This signature was then investigated in the gene expression profiles of normal B cells and found in pre- and post-GC B cells (naive and memory) but, surprisingly, not in GC B cells. This finding was validated in lymphoid tissues by showing that the nuclear factor- B (NF-B) transcription factors, which translocate to the nucleus upon CD40 stimulation, are retained in the cytoplasm in most GC B cells, indicating the absence of CD40 signaling. Nevertheless, a subset of centrocytes and B cells in the subepithelium showed nuclear staining of multiple NF-B subunits, suggesting that a fraction of naive and memory B cells may be subject to CD40 signaling or to other signals that activate NF-B. Together, these results show that GC expansion occurs in the absence of CD40 signaling, which may act only in the initial and final stages of the GC reaction. (Blood. 2004;104: 4088-4096)
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