CpG: unraveling the key to B-cell function

B cells were the first human immune cell subset known to recognize CpG motifs within microbial DNA in a CpG-specific manner. Based on B-cell activation and proliferation, the human CpG motif was identified and an oligo-nucleotide was developed (CpG ODN 2006) that induced the MAP kinase pathway and NFκB translocation in purified B cells, and that turned out to be a potent adjuvant to support humoral immune responses in primates (Hartmann and Krieg, J Immunol. 2000;164:944-953). But the important question of how CpG ODN acts on different levels of B-cell differentiation while maintaining antigen specificity remained elusive until recently, when Lanzavecchia's group reported that only memory B cells, and not naive B cells, proliferate and produce Ig in response to CpG ODN 2006 (Bernasconi et al, Science. 2002;298:2199-2202). In this issue, the same group (page 4500) extends these studies by demonstrating that naive B cells start to proliferate and to produce Ig in response to CpG ODN 2006 only if they receive simultaneous antigen-specific stimulation via the BCR.

Synergy of BCR ligation and CpG ODN has been described before but so far has not been studied in the context of B-cell subsets and TLR expression. Bernasconi and colleagues report here that TLR9 (the receptor required for recognition of CpG motifs) was low on naive B cells but high on memory B cells, and TLR9 mRNA was rapidly upregulated in naive B cells upon ligation of the BCR. The authors propose a model in which the level of TLR9 expression modulates the type of B-cell response. Although this conclusion is tempting, no formal evidence is provided for such a causative relationship between these 2 phenomena (upregulation of TLR9 and the B-cell differentiation). Not only memory but also naive B cells responded to CpG ODN in the absence of BCR ligation, although the naive B-cell response was limited to up-regulation of CD69 and CD86. Therefore, BCR ligation may trigger cellular events other than TLR9–up-regulation licensing naive B cells to proliferate and produce Ig in response to CpG. In this context it is interesting to note that in plasmacytoid dendritic cells (the other of the 2 CpG-sensitive immune cell subsets in humans), TLR9 expression is rapidly downregulated in the presence of the growth factor IL-3; still, CpG-mediated activation of plasmacytoid dendritic cells is even increased after preincubation with IL-3, suggesting that additional adaptor proteins modulated by IL-3 are involved in modulating the strength of the CpG-mediated response (Hornung et al, J Immunol. 2002;168:4531-4537).

As stated by Bernasconi and colleagues and evidenced by our own results, B cells are sensitive to CpG but not to LPS. The availability of CpG as the first defined microbial molecule recognized by human B cells leaves us with an avenue of new aspects of B-cell biology to be addressed, including B-cell malignancies (Jahrsdorfer et al, J Leukoc Biol. 2002;72:83-92).

Looking ahead, the interference of B cells with CD4 T-cell–derived CD40L and cytokines will be critical for the understanding of how self-tolerance is maintained in the situation in which B cells are costimulated with CpG ODN.