Toll-like receptor stimulation as a third signal required for activation of human naive B cells

Eur J Immunol. 2006 Apr;36(4):810-6. doi: 10.1002/eji.200535744.


According to the current model, naive B cell activation is dependent on the sequential integration of two signals: B cell receptor (BCR) cross-linking by antigen, followed by cognate interaction with helper T cells through an immunological synapse. Using an improved method to purify human naive B cells we found that BCR stimulation and T cell help induced initial cell division but were not sufficient to promote survival and differentiation thus leading to abortive proliferation of naive B cells. Extensive B cell proliferation, isotypic switch and differentiation to immunoglobulin (Ig)-secreting cells was induced by addition of microbial products that trigger any of the Toll-like receptors (TLR) that are up-regulated in naive B cells upon BCR triggering. TLR agonists acted directly on B cells and were required irrespective of the nature of the T helper cells present. Supernatants of dendritic cells (DC) stimulated by DC-specific TLR agonists were also capable of enhancing B cell responses although to a much lower and variable extent. These results indicate that human naive B cell activation is critically dependent on innate stimuli acting optimally on TLR expressed by B cells. The coupling of BCR stimulation to TLR expression endows the human system with a high degree of specificity since it allows focusing of innate signals only on antigen-stimulated B cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • Toll-Like Receptors / immunology*


  • Toll-Like Receptors