Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation

J Allergy Clin Immunol. 2012 Jun;129(6):1594-601.e2. doi: 10.1016/j.jaci.2012.03.014. Epub 2012 Apr 25.


Background: B cells are activated by combined signals through the B-cell receptor (BCR) and CD40. However, the underlying mechanisms by which BCR signals synergize with Toll-like receptor (TLR) signaling in human B cells remain unclear.

Objective: We sought to elucidate a role of spleen tyrosine kinase (Syk), a key molecule of BCR signaling, in TLR-mediated activation of human B cells.

Methods: Human naive and memory B cells were stimulated with combinations of anti-BCR, soluble CD40 ligand, and CpG. Effects of the Syk inhibitors on several B-cell functions and expression of TLR9, TNF receptor-associated factors (TRAFs), and phospho-nuclear factor κB in B cells were assessed.

Results: Activation of BCR synergized with CD40- and TLR9-mediated signals in driving robust proliferation, cell-cycle progression, expression of costimulatory molecules, cytokine production, and immunoglobulin production of human B-cell subsets, especially memory B cells. However, the Syk inhibitors remarkably abrogated these B-cell functions. Notably, after stimulation through all 3 receptors, B-cell subsets induced marked expression of TLR9, TRAF6, and phospho-nuclear factor κB, which was again significantly abrogated by the Syk inhibitors.

Conclusion: Syk-mediated BCR signaling is a prerequisite for optimal induction of TLR9 and TRAF6, allowing efficient propagation of TLR9-mediated signaling in memory B cells. These results also underscore the role of Syk in aberrant B-cell activation in patients with autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / cytology
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology*
  • CD40 Antigens / metabolism
  • Cell Cycle
  • Cell Differentiation / immunology
  • Cytokines / biosynthesis
  • Humans
  • Immunologic Memory
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation / immunology*
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction*
  • Syk Kinase
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptor 9 / metabolism
  • Toll-Like Receptors / metabolism*


  • CD40 Antigens
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, B-Cell
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase