Journal
JOURNAL OF IMMUNOLOGY
Volume 196, Issue 6, Pages 2591-2601Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501120
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Funding
- National Cancer Institute/National Institutes of Health [R01-CA157660]
- Stewart Trust Foundation
- Herbert Irving Comprehensive Cancer Center
- Cancer Biology Training Program fellowship (National Cancer Institute/National Institutes of Health 19 Grant) [5T32-CA009503-26]
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BAFF is critical for the survival and maturation of mature B cells. BAFF, via BAFFR, activates multiple signaling pathways in B cells, including the alternative NF-kappa B pathway. The transcription factors RELB and NF-kappa B2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B cell-intrinsic functions of these NF-kappa B subunits have not been studied in vivo using conditional alleles, either individually or in combination. We in this study report that B cell-specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nf kappa b2 caused a marked reduction. This phenotype was further exacerbated upon combined deletion of relb and nfkb2 and most dramatically affected the maintenance of marginal zone B cells. BAFF stimulation, in contrast to CD40 activation, was unable to rescue relb/nf kappa b2-deleted B cells in vitro. RNA-sequencing analysis of BAFF-stimulated nf kappa b2-deleted versus normal B cells suggests that the alternative NF-kappa B pathway, in addition to its critical role in BAFF-mediated cell survival, may control the expression of genes involved in the positioning of B cells within the lymphoid microenvironment and in the establishment of T cell-B cell interactions. Thus, by ablating the downstream transcription factors of the alternative NF-kappa B pathway specifically in B cells, we identify in this study a critical role for the combined activity of the RELB and NF-kappa B2 subunits in B cell homeostasis that cannot be compensated for by the canonical NF-kappa B pathway under physiological conditions.
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