Tracking CD40 signaling during germinal center development.
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-kappaB (NF-kappaB) 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-kappaB subunits, suggesting that a fraction of naive and memory B cells may be subject to CD40 signaling or to other signals that activate NF-kappaB. 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.
Basso
Katia
K
Institute for Cancer Genetics, Department of Pathology and Genetics and Development, Joint Centers for Systems Biology, Columbia University, 1150 St Nicholas Ave, New York, NY 10032, USA.
Klein
Ulf
U
Niu
Huifeng
H
Stolovitzky
Gustavo A
GA
Tu
Yuhai
Y
Califano
Andrea
A
Cattoretti
Giorgio
G
Dalla-Favera
Riccardo
R
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D018189:Immunomagnetic Separation; D015398:Signal Transduction / Q000276:immunology*
D019013:CD40 Antigens