Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 32, Pages 9063-9068Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1602728113
Keywords
germinal center B cell; plasma cell; NF-kappa B transcription factors
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Funding
- National Cancer Institute (NCI)/NIH Grant [R01-CA157660]
- Alexander and Margaret Stewart Trust (Washington, DC)
- Herbert Irving Comprehensive Cancer Center
- Cancer Biology Training Program Fellowship (NCI/NIH 19 Grant) [5T32-CA009503-26]
- German Research Council
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The NF-kappa B signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-kappa B in these cells. The NF-kappa B signaling cascade is comprised of two branches, the canonical and alternative NF-kappa B pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-kappa B2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-kappa B2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/ NF-kappa B2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-kappa B2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-kappa B pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.
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