To the editor:

We read with interest the recent paper by Liu et al. describing the observation that immunostimulatory CpG oligonucleotides induce the transcription factor T-bet in B cells, apparently leading to the suppression of immunoglobulin G1 (IgG1) and IgE isotype switching1. We were particularly interested in the potential implications of this observation to the pathogenesis of humoral autoimmunity, which seems to involve critical interactions between CpG sequences, Toll-like receptor 9 (TLR9) and T-bet2,3,4.

The authors and commentators conclude that CpG oligonucleotides suppress IgE and IgG1 through T-bet4. T-bet, however, is entirely dispensable for the ability of CpG oligonucleotides to suppress IgE and IgG1 in vitro, although it is essential for the production of IgG2a (Fig. 1 and data not shown). Indeed, the strongest evidence for T-bet seems to be in the promotion IgG2a class switching3. As such, the data of Liu et al. raise even more intriguing issues, as it would seem that T-bet mediates only one of the class-switching effects induced by TLR9 activation, and its expression, at least in the present context, reflects simply a marker of redirection to the IgG2a isotype. We propose that another transcriptional repressor, perhaps Bcl-6 (ref. 5) or Id2 (ref. 6), independently of T-bet, mediates the suppression of IL-4-related isotypes by CpG.

Figure 1: Immunoglobulin response to CpG oligonucleotides.
figure 1

B cells from T-bet-deficient (squares) or T-bet-sufficient (circles) C57BL/6 mice were incubated in culture for 10 d in the presence of antibody to CD40 and recombinant murine IL-4, in the presence (CpG) or absence (None) of stimulatory CpG oligonucleotides. Secreted IgE or IgG2a titers were determined by enzyme-linked immunosorbent assay. Results for IgG1 (data not shown) were analogous to those of IgE, presented here. *, titers below the limit of the assay (2.5 ng/ml). Each data point represents B cells isolated from one individual mouse; data are representative of three experiments, reflecting five to seven mice per genotype.

Full size image