Tracking CD40 signaling during germinal center development

• Published in: Blood Vol. 104; no. 13; pp. 4088 - 4096
• Main Authors: Basso, Katia, Klein, Ulf, Niu, Huifeng, Stolovitzky, Gustavo A., Tu, Yuhai, Califano, Andrea, Cattoretti, Giorgio, Dalla-Favera, Riccardo
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-12-2004; The Americain Society of Hematology
• Subjects: B-Lymphocytes - cytology; B-Lymphocytes - immunology; Biological and medical sciences; Burkitt Lymphoma; CD40 Antigens - physiology; Cell Line, Tumor; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Profiling; Gene Expression Regulation - immunology; Germinal Center - immunology; Humans; Immunobiology; Immunologic Memory; Immunomagnetic Separation; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Signal Transduction - immunology; Human; Lymphopoiesis; Signaling pathway; Germinative center; B-Lymphocyte; Transcription factor NFκB; Humoral immunity
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-12-4291

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-κB (NF-κB) 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-κB subunits, suggesting that a fraction of naive and memory B cells may be subject to CD40 signaling or to other signals that activate NF-κB. 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)