Role of TLR in B cell development: signaling through TLR4 promotes B cell maturation and is inhibited by TLR2

J Immunol. 2005 Jun 1;174(11):6639-47. doi: 10.4049/jimmunol.174.11.6639.

Abstract

The role of TLR4 in mature B cell activation is well characterized. However, little is known about TLR4 role in B cell development. Here, we analyzed the effects of TLR4 and TLR2 agonists on B cell development using an in vitro model of B cell maturation. Highly purified B220(+)IgM(-) B cell precursors from normal C57BL/6 mouse were cultured for 72 h, and B cell maturation in the presence of the TLR agonists was evaluated by expression of IgM, IgD, CD23, and AA4. The addition of LPS or lipid A resulted in a marked increase in the percentage of CD23(+) B cells, while Pam3Cys had no effect alone, but inhibited the increase of CD23(+) B cell population induced by lipid A or LPS. The TLR4-induced expression of CD23 is not accompanied by full activation of the lymphocyte, as suggested by the absence of activation Ag CD69. Experiments with TLR2-knockout mice confirmed that the inhibitory effects of Pam3Cys depend on the expression of TLR2. We studied the effects of TLR-agonists on early steps of B cell differentiation by analyzing IL-7 responsiveness and phenotype of early B cell precursors: we found that both lipid A and Pam3Cys impaired IL-7-dependent proliferation; however, while lipid A up-regulates B220 surface marker, consistent with a more mature phenotype of the IgM(-) precursors, Pam3Cys keeps the precursors on a more immature stage. Taken together, our results suggest that TLR4 signaling favors B lymphocyte maturation, whereas TLR2 arrests/retards that process, ascribing new roles for TLRs in B cell physiology.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Cysteine / analogs & derivatives*
  • Cysteine / antagonists & inhibitors
  • Cysteine / pharmacology
  • Growth Inhibitors / agonists
  • Growth Inhibitors / deficiency
  • Growth Inhibitors / metabolism
  • Growth Inhibitors / physiology*
  • Immunophenotyping
  • Ligands
  • Lipoproteins / antagonists & inhibitors
  • Lipoproteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Immunologic / agonists
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Stem Cells / cytology
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4

Substances

  • Growth Inhibitors
  • Ligands
  • Lipoproteins
  • Receptors, Immunologic
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • 2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine
  • Cysteine