Toll-like receptor stimulation as a third signal required for activation of human naive B cells.
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.
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Claudia R
CR
Ruprecht
Antonio
A
Lanzavecchia
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
D051193:Toll-Like Receptors