Liu replies:

We appreciate seeing the data promptly generated by Peng et al. As we were unable to obtain T-bet-deficient mice, we concluded1 that the CpG-induced up-regulation of T-bet correlated with the induction of IgG2a and the inhibition of IgE and IgG1. The data of Peng et al. confirmed our results and further clarified the T-bet-dependent IgG2a induction and T-bet-independent inhibition of IgE, directing the course of CpG-regulated humoral immunity to two scenarios.

The issue raised, then, is how CpG inhibits IL-4-induced IgE switching. It is not likely to be due to interference with tyrosine phosphorylation of STAT6 by Janus kinases1. Many possibilities still need to be tested, however. For example, serine phosphorylation of STAT6 prevents its binding to DNA, and the transcription factors NF-κB, AP-1, E2A, C/EBP, Bcl6 and Id2 also regulate IL-4-induced IgE switching2. Indeed, in an attempt to understand TLR9-mediated gene programming in B cells on a genomic scale, we found that CpG-TLR9 regulated a distinct set of transcription factors (data not shown). Notably, in many cases it results in transcriptional suppression through either down-regulation of transactivators or induction of transcriptional repressors. Identification of the molecules responsible for the CpG-mediated inhibition of IgE switching must await the results of biochemical and functional analyses.