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.

See accompanying commentary http://www.dx.doi.org/10.1002/eji.200636040