Reduced c-myc expression levels limit follicular mature B cell cycling in response to TLR signals

J Immunol. 2009 Apr 1;182(7):4065-75. doi: 10.4049/jimmunol.0802961.

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