Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 211, Issue 10, Pages 2103-2118Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132613
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Funding
- National Cancer Institute (NCI)/National Institutes of Health (NIH) [R01-CA157660]
- Stewart Trust Foundation (USA)
- HICCC
- German Research Council (DFG)
- Cancer Biology Training Program fellowship (NCI/NIH) [5T32-CA009503-26]
- Fondazione Cariplo (Italy)
- NIH [P60DK20541]
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Germinal centers (GCs) are the sites where memory B cells and plasma cells producing high-affinity antibodies are generated during T cell-dependent immune responses. The molecular control of GC B cell maintenance and differentiation remains incompletely understood. Activation of the NF-kappa B signaling pathway has been implicated; however, the distinct roles of the individual NF-kappa B transcription factor subunits are unknown. We report that GC B cell-specific deletion of the NF-kappa B subunits c-REL or RELA, which are both activated by the canonical NF-kappa B pathway, abolished the generation of high-affinity B cells via different mechanisms acting at distinct stages during the GC reaction. c-REL deficiency led to the collapse of established GCs immediately after the formation of dark and light zones at day 7 of the GC reaction and was associated with the failure to activate a metabolic program that promotes cell growth. Conversely, RELA was dispensable for GC maintenance but essential for the development of GC-derived plasma cells due to impaired up-regulation of BLIMP1. These results indicate that activation of the canonical NF-kappa B pathway in GC B cells controls GC maintenance and differentiation through distinct transcription factor subunits. Our findings have implications for the role of NF-kappa B in GC lymphomagenesis.
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