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.
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.
Katia
K
Basso
Ulf
U
Klein
Huifeng
H
Niu
Gustavo A
GA
Stolovitzky
Yuhai
Y
Tu
Andrea
A
Califano
Giorgio
G
Cattoretti
Riccardo
R
Dalla-Favera
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