Reduced c-myc Expression Levels Limit Follicular Mature B Cell Cycling in Response to TLR Signals

The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2009-04, Vol.182 (7), p.4065-4075
Main Authors: Meyer-Bahlburg, Almut, Bandaranayake, Ashok D, Andrews, Sarah F, Rawlings, David J
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Blotting, Western
Carrier Proteins - immunology
Carrier Proteins - metabolism
Cell Cycle - immunology
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases - immunology
Extracellular Signal-Regulated MAP Kinases - metabolism
Flow Cytometry
Gene Expression
Lipopolysaccharides - immunology
Lymphocyte Activation - immunology
Lymphocyte Subsets - immunology
Lymphocyte Subsets - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B - immunology
NF-kappa B - metabolism
Phosphotransferases (Alcohol Group Acceptor) - immunology
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Proto-Oncogene Proteins c-akt - immunology
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-myb - biosynthesis
Proto-Oncogene Proteins c-myb - immunology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - immunology
Spleen - cytology
Spleen - immunology
Toll-Like Receptors - immunology
Toll-Like Receptors - metabolism
TOR Serine-Threonine Kinases
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Summary:The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly delayed and reduced levels of proliferation to the identical stimulus. The current study was designed to identify a potential mechanism(s) accounting for this differential responsiveness. In contrast to the delay in cell cycle entry, FM and MZ B cells exhibited nearly identical LPS-driven alterations in the expression level of cell surface activation markers. Furthermore, both the NF-kappaB and mTOR signaling cascades were similarly activated by LPS stimulation in FM vs MZ B cells, while inducible activation of ERK and AKT were nearly absent in both subsets. MZ B cells, however, exhibited higher basal levels of phospho-AKT and pS6, consistent with a preactivated status. Importantly, both basal and LPS activation-induced c-myc expression was markedly reduced in FM vs MZ B cells and enforced c-myc expression fully restored the defective proliferative response in FM B cells. These data support a model wherein TLR responses in FM B cells are tightly regulated by limiting c-myc levels, thereby providing an important checkpoint to control nonspecific FM B cell activation in the absence of cognate Ag.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0802961