Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
-
TOR Serine-Threonine Kinases
-
Toll-Like Receptors / immunology*
-
Toll-Like Receptors / metabolism
Substances
-
Carrier Proteins
-
Lipopolysaccharides
-
NF-kappa B
-
Proto-Oncogene Proteins c-myb
-
Toll-Like Receptors
-
Phosphotransferases (Alcohol Group Acceptor)
-
mTOR protein, mouse
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases
-
Extracellular Signal-Regulated MAP Kinases